Nonparaneoplastic autoimmune cerebellar ataxias …

Neuroimmunology

Updated 03.28.2026
Released 08.23.2019
Expires For CME 03.28.2029

Nonparaneoplastic autoimmune cerebellar ataxias

Authors: Hiroshi Mitoma MD PhD, Mario Manto MD PhD, Marios Hadjivassiliou MD

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Editor: Francesc Graus MD PhD

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Nonparaneoplastic autoimmune cerebellar ataxias

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Introduction

Overview

Immune-mediated cerebellar ataxias are divided into paraneoplastic and nonparaneoplastic diseases. The latter include gluten ataxia, postinfectious cerebellitis, opsoclonus myoclonus ataxia syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. When autoimmunity is triggered by another condition (eg, gluten sensitivity in gluten ataxia), treatment priority should be given to removing the trigger. If this is not possible, or when autoimmunity is not caused by an obvious trigger, various combinations of immunotherapies can be used to prevent the progression of the ataxia. Immunotherapy should be initiated as soon as possible during the period of maintained cerebellar reserve, defined as the capacity to compensate for and restore neural function. Assuming immunotherapies arrest progression, the reversibility of ataxia depends on functional remodeling of the cerebellar circuitry, which is characterized by a high degree of plasticity. In general, prognosis is better for non-paraneoplastic immune-mediated cerebellar ataxias when therapies are initiated promptly, in contrast to the poor prognosis of paraneoplastic cerebellar degeneration. For successful intervention, a diagnosis of nonparaneoplastic immune-mediated cerebellar ataxia is necessary at the early stages of the disease before neuronal loss compromises cerebellar reserve.

Key points

	• Nonparaneoplastic immune-mediated cerebellar ataxias include diverse etiologies.
	• Nonparaneoplastic immune-mediated cerebellar ataxias are characterized by subacute onset, frequent autoimmune disease history in the patient or relatives, and predominant gait ataxia, usually associated with autoantibodies.
	• Immunotherapy should be considered when the underlying trigger is not identified or cannot be removed.
	• Immunotherapies should be introduced during the period of maintained cerebellar reserve, defined as the capacity for compensation and restoration of cerebellar function.

Historical note and terminology

Various pathologies can cause cerebellar insult, leading to cerebellar ataxias and resulting in motor and cognitive incoordination. The documentation of immune-mediated cerebellar ataxias originates from a classical work by Charcot JM. One historical milestone was Brouwer’s report in 1919, which described the association of cerebellar ataxias with ovarian tumors and was the first report of paraneoplastic cerebellar degeneration. Two further breakthroughs occurred in the 1980s. First, an autoantibody against the Purkinje cells, later named anti-Yo, was described in a patient with an ovarian tumor associated with cerebellar ataxia. The identification of other specific autoantibodies followed, including anti-Hu, anti-Tr, anti-CV2, anti-Ri, anti-Ma2, and anti-VGCC, which are shown to be associated with specific types of neoplasms, especially breast, uterine, and ovarian cancers, as well as small-cell lung carcinoma and Hodgkin lymphoma. At present, there is general agreement that autoimmunity triggered by the neoplasm results in cerebellar ataxias.

The association of otherwise idiopathic cerebellar ataxias with autoantibodies against the cerebellum was subsequently reported in patients without evidence of cancer (26; 45; 44; 46; 47; 28; 27; 25). Two main clinical entities have been established based on specific clinical features and type of associated autoantibodies: gluten ataxia and anti-glutamic acid decarboxylase 65 (GAD 65) antibody-associated cerebellar ataxia (anti-GAD ataxia).

Clinical manifestations

Presentation and course

Although the etiology is diverse, nonparaneoplastic immune-mediated cerebellar ataxias share some common clinical phenotypes. The onset of cerebellar ataxias is usually acute/subacute. The presence of other autoimmune disorders in the patient or first-degree relatives is common. The main symptom is gait ataxia, which hinders gait, standing, and steady walking due to the preferential involvement of the vermis. Other manifestations include variable degrees of limb incoordination, dysarthria, and nystagmus. MRI may be normal or show atrophy primarily in the vermis, depending on disease duration. CSF pleocytosis or oligoclonal bands are sometimes observed (47).

There is no consensus on the classification of immune-mediated cerebellar ataxias. We have proposed a classification based on (1) whether the cerebellum is the main target of autoimmunity or not, and (2) whether autoimmunity is triggered by other conditions or not (44; 47). In cerebellar ataxias associated with connective tissue diseases, the cerebellum is one of many targets of autoimmune attack, and these ataxias are usually associated with other extracerebellar symptoms. On the other hand, when the cerebellum is the sole target of autoimmunity, the immune-mediated cerebellar ataxias are categorized into two groups: those where autoimmunity is triggered by other conditions, such as infection (eg, postinfectious cerebellitis) and gluten sensitivity (gluten ataxia), and those where autoimmunity has no obvious triggers (eg, anti-GAD ataxia). Another clinical entity, primary autoimmune cerebellar ataxia, was proposed by Hadjivassiliou and colleagues (21). Cerebellar ataxias are diagnosed as primary autoimmune cerebellar ataxia when immune-mediated mechanisms are strongly suspected, but no underlying trigger or pathogenic autoantibodies are identified. Thus, this group is likely heterogeneous and probably includes several autoimmune etiologies that await characterization.

Prognosis and complications

Immune-mediated cerebellar ataxia clinical course

(A) Six clinical courses of immune-mediated cerebellar ataxias: (a) full recovery, (b) partial recovery, (c) stabilization, (d) relapse, (e) gradually progressive, and (f) rapidly progressive. PIC: postinfectious cerebellitis; OMS...

Based on the response to treatment, the clinical course can be classified into six patterns (45; 47). In patterns (a)-(c), immunotherapy can stop the progression, whereas patterns (e)-(f) show no therapeutic benefits. The difference among these groups reflects the effects of immunotherapy on the different autoimmune processes. Notably, although immunotherapy can stop the progression (patterns (a)-(c)), the subsequent prognosis is mixed, ranging from different patterns of recovery (a) (full recovery) and (b) (partial recovery) to no recovery in pattern (c) (stabilization). Thus, the scheme indicates that the outcome of any therapy depends on two factors: the responsiveness to immunotherapy and the presence of cerebellar reserve. The latter is determined by the degree of damage, suggesting the existence of a threshold. Above such a threshold, ataxia can recover if immunotherapy can stop the disease process. In contrast, below this threshold, although the disease process can be stopped, cerebellar ataxias remain unchanged, and the patient remains disabled. Based on this recoverability, we introduced the concept of restorable (presence of cerebellar reserve) and nonrestorable stage, which can be viewed as a cerebellar circuitry, which can be recovered or not in terms of functionality (no cerebellar reserve) (49; 47).

Clinical vignette

A 58- year-old woman developed progressive unsteadiness of gait, vertigo, and oscillopsia related to postural head changes during the past year. Her medical history was significant for type 1 diabetes mellitus diagnosed at age 45 years, which required insulin treatment at 6 months after diagnosis, and psoriasis at age 38 years. General examination was normal except for psoriasis. The neurologic examination disclosed downbeat vertical nystagmus and ataxic gait. The remainder of her neurologic examination was normal. MRI showed type 1 Arnold-Chiari malformation. Routine laboratory analysis, including thyroid function tests were normal. Over the ensuing 2 years she noticed progressive dysarthria, and her gait became more unsteady. Clinical progression was initially believed to be related to the Chiari malformation, and the patient underwent posterior suboccipital decompression. After surgery, her dysarthria and downbeat nystagmus improved, but not her gait. Over the ensuing 3 years, she developed clumsiness of the right hand and increasing unsteadiness. Neurologic examination revealed mild dysarthria, upward vertical nystagmus, limb dysmetria more marked on the right, and severe ataxic gait that prevented her from walking alone more than a few meters. MRI demonstrated resolution of cerebellar tonsillar descent and mild atrophy of the vermis. The following organ-specific autoantibodies were detected: pancreatic islet-cell, gastric parietal cell, and thyroid microsomal antibodies; adrenal glands and thyroglobulin antibodies were negative. Whole-body CT scan was normal. CSF examination was normal except for the presence of oligoclonal IgG bands. High levels of GAD antibodies were confirmed in the serum and CSF with a ratio compatible with intrathecal synthesis of GAD antibodies. The patient was treated with multiple courses of intravenous immunoglobulins, azathioprine, and rituximab without improvement. At the last visit, 15 years after the onset of the ataxia, she was wheelchair bound with a severe pancerebellar syndrome.

Comment. This patient showed a poor response to immunotherapies. One should note that the disorder was evolving for at least 2 years. If diagnosis was delayed (partly because the Chiari malformation may have been the cause), neuronal loss occurred inevitably, with negative consequences on the cerebellar reserve. This case suggests the utmost importance of early diagnosis and therapy (time is cerebellum).

Epidemiology

The study by Hadjivassiliou and colleagues is the only large-scale investigation of the prevalence of immune-mediated cerebellar ataxias (26). Based on a study performed at the Sheffield Ataxia Centre, United Kingdom, of 1500 patients with progressive ataxia, the authors reported that 30% had definite immune-mediated cerebellar ataxias, 25% had gluten ataxia, and 3% had primary autoimmune cerebellar ataxia, whereas 2% had anti-GAD ataxia (Table 1).

A single-center study in China identified patients with autoimmune cerebellar ataxia encompassing paraneoplastic cerebellar degeneration (30.7%), primary autoimmune cerebellar ataxia (37.8%), autoimmune cerebellar ataxia associated with autoimmune encephalitis (12.6%), anti-GAD-associated ataxia (8.7%), Miller Fisher syndrome (7.1%), and opsoclonus myoclonus syndrome (3.1%) (39).

Gebus and colleagues reported a smaller number of patients with isolated vermian pathology (two with paraneoplastic cerebellar degeneration and one patient with postinfectious cerebellitis among 80 patients) (17). In a systematic study of 684 South Korean patients with progressive ataxia, only 21 had isolated vermian pathology; 14 had paraneoplastic cerebellar degeneration, three had postinfectious cerebellitis, and four had other immune causes (35).

A single-institution study in Japan reported that among 243 patients with cerebellar ataxias as the primary neurologic symptom, 13 were diagnosed with autoimmune cerebellar ataxia (36). Of these 13 patients, five were classified as paraneoplastic and eight as non-paraneoplastic.

Table 1. Clinical Profiles of Common Etiologies of Nonparaneoplastic Immune-Mediated Cerebellar Ataxias

	Gluten ataxia	Postinfectious cerebellitis	Opsoclonus myoclonus ataxia syndrome	Anti-GAD ataxia	Primary autoimmune cerebellar ataxia
Prevalence amongst cerebellar ataxias	20%	1%	0.8%	2%	Unknown (amongst 20% of idiopathic sporadic ataxias)
Autoimmune background
Trigger of autoimmunity	Gluten ingestion	Children: varicella, vaccination. Adults: Epstein-Barr virus, mycoplasma, enterovirus, Borrelia burgdorferi	Paraneoplastic (neuroblastoma) Postinfectious, Primary autoimmune	Unknown	Unknown
HLA	DQ2 or DQ8	-	-	-	DQ2
Well-characterized antibodies	Gliadin (IgG/IgA), TG2, TG6	None	Ri (for paraneoplastic)	Anti-GAD65 (high titer)	None
Less well-characterized antibodies	-	Anti-Gluδ2		-	Anti-Cerebellum (immunohistochemistry) GAD65 (low titer), Homer3, Gluδ2
Associated autoimmune diseases	Celiac disease (47%), diabetes mellitus type 1, thyroiditis, pernicious anemia	-	-	Diabetes mellitus type 1, pernicious anemia	Thyroiditis, Sjögren syndrome, diabetes mellitus type 1, primary biliary cirrhosis, pernicious anemia, vitiligo
Clinical profile
Time course	Insidious and chronic	Acute	Subacute	Chronic or subacute	Insidious and chronic
Age and gender	40s to 50s, females (55%)	Mainly children, rarely adults	Mainly children, rarely adults	60s, females (mostly)	50s
Main cerebellar symptom	Gait ataxia	Gait ataxia	Opsoclonus myoclonus	Gait ataxia	Gait ataxia
Associated neurologic symptoms	Cortical myoclonus, neuropathy	-	-	Epilepsy, stiff-person syndrome	-
Cerebrospinal fluid	Normal	High white blood cell count. High IgG levels in 50%, oligoclonal bands in some	Sometimes; high white blood cell count and protein level	Sometimes; oligoclonal bands	Not studied
Cerebellar atrophy on MRI	Present depending on duration of ataxia	None	None	Depending on duration of ataxia	Depending on duration of ataxia

Prevalence amongst all progressive cerebellar ataxias is cited from references (44; 47; 27).

Differential diagnosis

Immune-mediated cerebellar ataxias have diverse etiologies. Here we review detailed clinical features and discuss differential diagnosis (Table 1).

Common etiologies in nonparaneoplastic immune-mediated cerebellar ataxias

Gluten ataxia. Gluten ataxia is defined as sporadic cerebellar ataxia associated with gluten sensitivity. This is by far the most common immune-mediated cerebellar ataxia and one of the few with a known antigenic stimulus (gluten proteins) (27).

Gluten ataxia affects mainly women (55%) with a mean age of 52 years and exhibits either chronic or insidious onset (23; 27). Gluten-sensitive enteropathy or gastrointestinal manifestations are seen in about half (47%) of the patients. The HLA type DQ2 is detected in 70% of the patients, and association with other autoimmune diseases, such as thyroiditis, type 1 diabetes mellitus, and pernicious anemia, is common. Gluten ataxia is sometimes associated with sensorimotor axonal neuropathy and is less common with focal myoclonus and palatal tremor. Patients present with gait ataxia and variable degrees of limb ataxia, scanning speech, and ocular ataxia; MRI and MR spectroscopy consistently show vermian involvement (23). Up to 50% of patients with gluten ataxia have CSF abnormalities (23; 27).

Gluten sensitivity is assessed using autoantibody assays. Because anti-transglutaminase 2 antibodies, found in patients with celiac disease, are negative in 53% of patients with gluten ataxia without enteropathy (29), this antibody is not sufficient to diagnose gluten ataxia. Anti-gliadin antibodies (IgG and IgA) are reliable for the diagnosis (27); however, the cutoff level and utility of different assays should be noted. In patients with gluten ataxia without enteropathy, the main autoimmune responses occur within the CNS, resulting in low levels of serum anti-gliadin antibodies (27). The calibration process used in certain commercially available anti-gliadin antibody kits is based on the use of serum from patients with celiac disease; therefore, the cutoff level is too high for the detection of gluten ataxia (27). Anti-transglutaminase 6 antibody, a brain-expressed transglutaminase, is positive in 72% of patients with gluten ataxia as defined by positivity for anti-gliadin antibodies. Because anti-transglutaminase 6 is primarily expressed in the CNS, anti-transglutaminase 6 antibodies could be an important specific biomarker (27).

In some cases, the neurologic deterioration can be rapid and devastating, mimicking postinfectious cerebellitis and paraneoplastic cerebellar degeneration (55). This atypical subtype requires prompt diagnosis and rapid intervention (using immunosuppression as well as gluten free diet) in order to avert severe and permanent neurologic disability.

A gluten-free diet is considered an effective therapy for gluten ataxia, based on avoidance of antigens that can trigger immune-mediated mechanisms, similar to the strategy used in celiac disease (23; 27). In a study involving 43 patients with gluten ataxia, significant improvements in cerebellar ataxia and a decrease in anti-gliadin antibodies were noted in patients who adhered to a gluten-free diet compared with those who refused a gluten-free diet (29). Other reports described the effectiveness of intravenous immunoglobulins in patients with resistance to a gluten-free diet. It is now considered that resistance to a gluten-free diet is due to either poor adherence to a gluten-free diet or hypersensitivity to even small amounts of gluten present in some commercially available gluten-free food, or due to cross-contamination (27). MR spectroscopy can also be used to detect the effects of a gluten-free diet (23). Patients on a strict gluten-free diet show an increase in the relative N-acetylaspartate/creatine (NAA/Cr) area in the cerebellar vermis, whereas no such increase is noted in patients on a gluten-free diet with persistently positive antibodies and those who do not adhere to a gluten-free diet. Taken together, in patients with persistently high anti-gliadin antibody titers or no changes in MR spectroscopy, strict adherence to a gluten-free diet should be considered before switching to immunotherapy. When cerebellar ataxias cannot be controlled with a gluten-free diet, maintenance therapy with immunosuppressants (eg, mycophenolate mofetil and rituximab) is recommended (23; 27).

Cerebellar ataxias associated with cortical myoclonus are a rare subtype of gluten sensitivity-related neurologic disorder (58). Although the myoclonus is of cortical origin, hyperexcitability of the cerebral cortex is elicited by the cerebellar pathology (58). Characteristically, this subtype shows resistance to a gluten-free diet. The neurologic refractoriness is associated with residual enteropathy, which is detected by repeat duodenal biopsies (58). Some of these patients have refractory celiac disease type 2 and are at high risk of development of enteropathy-associated lymphoma (58). Based on these features, this condition is termed "neurologically refractory" celiac disease (27). All such patients require a gluten-free diet plus immunosuppression, usually with mycophenolate and, in some instances, cladribine, in addition to anti-epileptic drugs (levetiracetam, perampanel, and clonazepam) for the control of the myoclonus (58). The prognosis remains poor (58).

Postinfectious cerebellitis. Infection-induced cerebellar ataxias are classified into two categories: (1) inflammation caused by direct invasion of viral or bacterial microorganisms, and (2) inflammation induced by immune mechanisms triggered by the infection (02; 27; 47). Some groups termed the former type "acute cerebellitis" and the latter as post- or para-infectious cerebellitis, postinfectious cerebellar ataxia, or acute cerebellar ataxia (02). The latent interval of several days to weeks is reminiscent of a delayed antigen-antibody reaction. Postinfectious cerebellitis affects mostly young children after an episode of infection, usually a viral infection, most commonly varicella) (08; 02). Other etiologies include viral infections, such as Epstein-Barr virus, Coxsackie virus, influenza A and B viruses, parainfluenza virus, measles, mumps, and rubella, and bacterial infections, such as diphtheria, pertussis, typhoid, Legionnaires disease, leptospirosis, Borrelia, and mycoplasma (02). Based on a systematic survey of 73 patients (08), 60% of the patients were between 2 and 4 years of age. Furthermore, 25% of the children had varicella, 52% had other viral infections, and 3% developed postinfectious cerebellitis after immunization. The mean latency between infection and the onset of cerebellar ataxias was 9.9 ± 7.9 days, although it should be noted that 19% of the patients did not exhibit any preceding infection.

The main clinical feature of acute-onset cerebellar ataxias is gait ataxia (08). Patients are usually afebrile and do not show meningeal signs, high intracranial pressure, or extracerebellar manifestations, such as temporary clouding of consciousness, seizures, extremely altered mental status (eg, extreme irritability), or cerebral focal signs (08). Rather, the presence of these clinical signs is suggestive of inflammation induced directly by infection rather than inflammation induced by autoimmunity. However, mild behavioral changes, such as mild irritability, hyperactivity, moodiness, and whining, are sometimes noted by parents; the behaviors correlate with the severity of cerebellar ataxias, suggesting cerebellar involvement in cognitive and emotional disorders. CSF examination shows pleocytosis (roughly equal numbers of granulocytes and lymphocytes in about 75% of the patients and sometimes lymphocyte predominance in the remaining cases) and a high CSF/serum IgG index in half of the children. Oligoclonal bands are sometimes present (08). MRI usually shows no atrophy or areas of abnormal intensity.

Because postinfectious cerebellitis is self-limiting, close monitoring of the patient and follow-up form the basis of clinical management (47). Only when the cerebellar ataxia persists or progresses should a combination of immunotherapies be considered (02). However, one has to bear in mind that some other immune-mediated ataxias may present very similarly to acute cerebellitis and, therefore, the absence of improvement and evidence of progression should raise the possibility of another immune-mediated ataxia. One large-scale study of 60 pediatric patients showed full recovery of the gait ataxia in 72% of patients, within about 2 months in most cases (08). Despite a favorable prognosis in the majority of cases, some patients develop permanent sequelae, especially in the elderly. The possibility of swelling of the cerebellum with hydrocephalus should be kept in mind.

Myoclonus and cerebellar ataxias associated with COVID-19. One systematic review examined the association of myoclonus and cerebellar ataxia (05). The authors identified 51 patients from surveys on reports published from November 1, 2019, to December 6, 2020. The mean age was 59.6 years, ranging from 26 to 88 years, and 21.6% were female. The median latency between COVID-19 symptoms and myoclonus/cerebellar ataxias was 13 days. Myoclonus and cerebellar ataxias had an acute onset, usually within 1 month of COVID-19 symptoms. Among these 51 patients, 23.5% (12 out of 51) of cases had myoclonus and cerebellar ataxias, 35.3% (18 out of 51) of cases had myoclonus without cerebellar ataxias, and 41.2% (21 out of 51) of cases had cerebellar ataxias. Myoclonus was multifocal or generalized, activated by action in 56.7% (17 out of 30) of cases and by sensory stimuli in 46.7% (14 out of 30) of cases. Myoclonus and cerebellar ataxias were concurrently associated with other neurologic symptoms, including cognitive changes (45.5%) or a Miller Fisher syndrome variant (21.2%).

Eighty percent (24 out of 30) of cases reported improvement or resolution of these neurologic symptoms within 2 months, either spontaneously or with antiepileptic therapies and immunotherapies, including methylprednisolone and IVIg.

Opsoclonus myoclonus syndrome. Opsoclonus myoclonus syndrome shows opsoclonus (repetitive, involuntary, random, and rapid eye movements in both horizontal and vertical directions) and action myoclonus, with subacute onset (01). Opsoclonus myoclonus syndrome affects primarily children, whereas it is rare in adults(01). Opsoclonus myoclonus syndrome is classified into three types: paraneoplastic, postinfectious, and idiopathic (27; 47).

Postinfectious opsoclonus myoclonus syndrome is self-limiting, whereas idiopathic opsoclonus myoclonus syndrome shows spontaneous recovery in some patients (01; 27; 47). Immunotherapy should be used in patients with persistent or progressive symptoms (01; 27; 47). Several studies investigated the differences in prognosis between paraneoplastic and idiopathic opsoclonus myoclonus syndrome, which demonstrated good response to therapy, defined by a modified Rankin Score of 2 or less, in 39% of patients with paraneoplastic opsoclonus myoclonus syndrome and 84% of those with idiopathic opsoclonus myoclonus syndrome (01).

Anti-GAD ataxia. This condition mostly affects women (82%) in their 60s, with a subacute, chronic, or insidious time course (46; 48; 19). Autoimmune diseases, such as type 1 diabetes mellitus, autoimmune thyroid diseases, and pernicious anemia, are associated with anti-GAD cerebellar ataxias in at least some cases. Cerebellar ataxias are sometimes associated with extracerebellar symptoms, including temporal lobe epilepsy, limbic encephalitis, ophthalmoplegia, opsoclonus, and stiff-person syndrome. The overlap syndromes are observed during follow-up and over the years in 14% to 36% of the patients with cerebellar ataxia (09). Cases positive for anti-GAD antibodies have also been reported, with initial cerebellar ataxia followed by progressive encephalomyelitis with rigidity and myoclonus (PERM) (32). Some patients show oligoclonal bands in the CSF, whereas MRI shows normal or atrophic changes depending on the duration of illness (46; 48; 09).

A genetic predisposition to neurologic disorders associated with anti-GAD65 antibodies has been suggested. A systematic study reported that 68% (44/95) of patients had a family history of autoimmunity, including 55.4% (36/65) of first-degree relatives; the sibling recurrence risk (λS) was 5.5 (53). However, 32.3% (21/65) of patients had no identified family history of autoimmunity, suggesting a variable and heterogeneous genetic predisposition to anti-GAD65 Ab-related neurologic disorders.

The significance of anti-GAD65 antibodies has been a matter of debate, with some researchers arguing that these antibodies have no pathogenic roles for the following three reasons (48; 42; 09; 19). First, GAD65 is an intracellular antigen. Second, anti-GAD65 antibodies are associated with type 1 diabetes mellitus and other neurologic diseases, such as epilepsy, limbic encephalitis, ophthalmoplegia, and stiff-person syndrome (14). Finally, passive transfer studies failed to mimic neurologic symptoms. For example, cerebroventricular or intrathecal administration of IgG from stiff-person syndrome patients has not consistently elicited stiff-person syndrome-like symptoms (19). When animals were immunized with human GAD65, no neurologic symptoms were observed (06). On the other hand, accumulated physiological evidence suggests a pathogenic role for anti-GAD65 antibodies in the development of cerebellar ataxias, which is explained below (41).

Treatment. Previous studies showed that some patients respond well to immunotherapies and that the clinical improvement in cerebellar ataxia correlates well with the fall in Ab titers (45; 49). These findings indicate that Ab titers better reflect functional disorders rather than cell death.

The aim of any induction therapy is to minimize cerebellar ataxias, which includes various immunotherapies, ranging from intravenous immunoglobulins, glucocorticosteroids, immunosuppressants, plasmapheresis, and rituximab, either alone or in combinations (45; 47; 19). Furthermore, maintenance therapies (eg, oral prednisolone, intravenous immunoglobulins, immunosuppressants, or rituximab, alone or in combination) are also recommended to prevent relapse (45; 47). Because anti-GAD65 ataxia exhibits a chronic time course, the efficacy and therapeutic dose of prednisolone should be monitored carefully to avoid side effects (47). In this regard, it seems there are no significant differences in the response to each type of the above immunotherapies (45; 47). A decrease in anti-GAD65 antibody level during the treatment can be used as a therapeutic index (47). Evidence suggests that prognosis is better in the subacute type than in the chronic type of anti-GAD ataxia.

Interestingly, 35 of the 50 patients with anti-GAD antibodies (70%) had evidence of gluten sensitivity. Half of them showed a therapeutic response to a gluten-free diet, suggesting considerable overlapping between gluten ataxia and anti-GAD ataxia (30).

Primary autoimmune cerebellar ataxia. Despite their autoimmune nature (eg, subacute onset, autoimmune disease history, predominant gait ataxia, association with autoantibodies, and good benefits from immunotherapies), some cerebellar ataxias do not fit into the above categories. In these cases, the autoimmune condition is considered within the spectrum of primary autoimmune cerebellar ataxia (44; 27), which was originally proposed by Hadjivassiliou and colleagues (21). Notably, patients with primary autoimmune cerebellar ataxia predominantly show HLA type DQ2, which predominates in certain autoimmune diseases (celiac disease, gluten ataxia, type1 diabetes mellitus, stiff-person syndrome, autoimmune thyroid disease, and autoimmune polyendocrine syndromes) (27). No definite antigens are known to trigger the autoimmune insult in the cerebellum. Various types of less well-characterized autoantibodies are associated in some patients (Table 1) (21).

Patients diagnosed with primary autoimmune cerebellar ataxia usually develop clinically evident cerebellar ataxia in their early 50s (27). The cerebellar ataxia, mainly gait ataxia, exhibits a slowly progressive course, which is not as slow as in degenerative cerebellar ataxias. Although some patients who show a subacute clinical course have been misdiagnosed with postinfectious cerebellitis, they do not show self-limiting improvement, which characterizes postinfectious cerebellitis. MRI at presentation can be normal or show vermian atrophy, whereas MR spectroscopy can show preferential and sometimes exclusive involvement of the vermis at early stages (22). The proposed diagnostic criteria stress three stages: (1) exclusion of immune-mediated cerebellar ataxias with a known trigger factor (eg, paraneoplastic cerebellar degeneration, gluten ataxia, percutaneous coronary intervention) and exclusion of immune-mediated cerebellar ataxias with characterized pathogenic autoantibodies (such as anti-mGluR1); (2) satisfying at least two of the following conditions: pleocytosis and/or oligoclonal bands in CSF, history and/or family history of autoimmune diseases, and presence of autoantibodies showing autoimmunity (these can be against any organ, eg, thyroid); and (3) exclusion of alternative causes for ataxia (22).

A small number of studies described more beneficial effects of immunotherapies (intravenous immunoglobulins, prednisolone, plasmapheresis, or rituximab) in patients at the subacute phase (four of six patients) than in patients at the chronic stage (nine of nine patients). Another retrospective study based on 118 patients with immune-mediated cerebellar ataxias (55 patients with nonparaneoplastic immune-mediated cerebellar ataxias) showed that 55 of these patients responded well to immunotherapies, and the improvement was more prominent in nonparaneoplastic patients (33). The progression to wheelchair dependence was faster in patients with neuronal nuclear or cytoplasmic antibody than those positive for plasma membrane protein antibody. MR spectroscopy of the cerebellum seems to be an important tool in monitoring the response to immunotherapies (27). Notably, a systematic study on 22 patients with primary autoimmune cerebellar ataxia revealed that mycophenolate had therapeutic benefits in the SARA score, which was associated with an improvement in MR spectroscopy (an increase in the NAA/Cr ratio of the cerebellar vermis) (24).

Latent autoimmune cerebellar ataxia. The concept of latent autoimmune cerebellar ataxia (LACA) was introduced, drawing parallels with latent autoimmune diabetes in adults (LADA). Type 1 diabetes is defined by the immune-mediated destruction of pancreatic Langerhans' β-cells by an immune mechanism, leading to insulin secretion failure. However, a subset of this population exhibits a gradual decline in insulin secretion and initially ambiguous autoimmune characteristics, complicating the diagnosis of type 1 diabetes. This subset has been classified as latent autoimmune diabetes in adults.

In a similar vein, among latent autoimmune cerebellar ataxias, a subset has been empirically observed to follow a slow progression or present ambiguous autoimmune manifestations, such as well-characterized autoantibodies. Some patients exhibit only mild instability and eye movement disturbances, without overt cerebellar ataxias, and with poorly characterized autoantibodies. Consequently, these patients do not meet the diagnostic criteria for primary autoimmune cerebellar ataxia. However, their symptoms improved with immunotherapies, leading to a final diagnosis of immune-mediated cerebellar ataxias.

We, therefore, proposed the term latent autoimmune cerebellar ataxia and suggested the following diagnostic criteria (40):

	1) An autoimmune etiology is suspected.
	2) The ataxia is subclinical or so mild that it is difficult to detect on clinical examination, and nonspecific symptoms or other noncerebellar neurologic manifestations may precede the manifestation of ataxia. This stage can be retrospectively identified as prodromal.

By definition, latent autoimmune cerebellar ataxia is likely to follow a course of slow progression. Ultimately, the autoimmune mechanisms will affect the cerebellum, resulting in clinical cerebellar ataxias and eventually marked cerebellar atrophy.

Thus, “the notion of LACA is introduced to encourage clinicians to carefully examine the possibility of slow-evolving autoimmune cerebellar ataxia, as well as to stress the importance of the early intervention of immunotherapies during a period when there is cerebellar reserve” (40).

Rare etiologies in nonparaneoplastic immune-mediated cerebellar ataxias

The conditions described herein are less prevalent, and although cerebellar ataxias can be a prominent feature, these are frequently classed amongst a range of other neurologic disorders. Cerebellar ataxic deficits are often part of a more global neurologic syndrome.

Miller Fisher syndrome. The main disabling clinical features of Miller Fisher syndrome are ophthalmoplegia and ataxia. At the onset, patients generally exhibit diplopia, ptosis, and gait ataxia with only minor sensory symptoms (27). The ophthalmoplegia initially presents as a symmetrical failure of upgaze, followed by lateral gaze, and finally, failure of downgaze. The gait ataxia is often prominent. Nerve conduction is generally normal, despite the pathological evidence of axonal or demyelinating sensory neuropathy. CSF examinations often show high protein levels. Up to 90% of patients with Miller Fisher syndrome have high serum titers of anti-GQ1b Ab. Because this is not found in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, a positive anti-GQ1b Ab is considered a specific marker of Miller Fisher syndrome (44). Furthermore, anti-GQ1b Ab cross-reacts with epitopes present in the lipopolysaccharide of Miller Fisher syndrome-associated Campylobacter jejuni strains, suggesting molecular mimicry.

In general, Miller Fisher syndrome is a mild and self-limiting disease, thus requiring no immunotherapy (27). Although some reports have described the benefits of corticosteroids, intravenous immunoglobulins, and plasmapheresis, there are no significant differences in the speed of recovery and the final outcome between patients who receive immunotherapies, including intravenous immunoglobulins and plasmapheresis, and those treated conservatively (50).

Anti-voltage-gated Ca2+ channel (VGCC) ataxia. Anti-P/Q type VGCC Ab (anti-VGCC Ab) is found in paraneoplastic cerebellar degeneration associated with small cell lung cancer but has also been identified in patients with no cancer. One study reported the presence of anti-VGCC Ab in eight of 67 patients who showed chronic cerebellar degeneration (03). However, the VGCC Ab titers were not high, casting doubts on its clinical relevance.

Anti-DPPX ataxia. Encephalitis associated with anti-DPPX is characterized by agitation, mild confusion, hyperekplexia, myoclonus, trunk stiffness, and cerebellar ataxias (62). These clinical features suggest hyperexcitability of the CNS, which could be attributed to dysfunction of the potassium channel. Patients often complain of digestive symptoms (ie, pain, diarrhea). Because cerebellar ataxias with myoclonus can be the sole manifestation in this entity, the combination of these manifestations should be examined by measurement of anti-DPPX Ab (27). The response to immunotherapy is generally good, but long-term and aggressive treatment may be required in some patients (62).

Anti-Caspr2 ataxia. Contactin-associated protein-like 2 (Caspr2) is an associated protein of the voltage-gated K+ channel (VGKC) Kv1. A retrospective study identified stereotypic episodes of paroxysmal cerebellar ataxias in five of 20 patients (34). The ataxic episodes, including gait imbalance, limb ataxia, and slurred speech, usually last a few minutes to a few days and usually improve following immunotherapy. Interestingly, the permanent cerebellar ataxias and episodic ataxias are not associated with neuromyotonia or Morvan syndrome but are associated with limbic encephalitis (34; 52). Anti-Caspr2 is classified into these two groups—limbic-predominant group and peripheral nerve hyperexcitability-predominant group without overlapping (34; 52). In a comparative study of neurologic symptoms associated with anti-Caspr2 and LGI1 Abs, 149 patients with anti-Caspr2 Ab-associated encephalitis exhibited a higher prevalence of movement disorders and/or ataxia compared to 105 patients with anti-LGI1 Ab-associated encephalitis (35.6% vs. 3.8%) (18).

Anti- Leucine-rich glioma-inactivated 1 (LGI1) ataxia. LGI1 is a major antigen in autoimmune limbic encephalitis but rarely in immune-mediated cerebellar ataxias. One study identified motor disorders, including cerebellar ataxia, in seven of 34 patients; it did not include detailed clinical information (54). One case report described a young adult with predominant gait ataxia associated with disinhibited behaviors and visual hallucinations (61).

Anti-IgLON5 ataxia. The main clinical feature of anti-IgLON5 ataxia is gait instability. Although disequilibrium was documented as the reason for the instability, the exact mechanism remains unclear. The gait instability was attributed to cerebellar dysfunction in some patients (15). Notably, postmortem examination showed a novel neuronal tauopathy predominantly involving the hypothalamus and brainstem tegmentum (57). The prognosis was poor. No association with malignancy was documented. Only 10% of the patients demonstrated mild and transient improvement following immunotherapy with corticosteroids and IVIg (16).

Anti-AMPA R ataxia. Anti-AMPA receptor encephalitis typically manifests as limbic encephalitis (31). Notably, cerebellar ataxia was observed in 14% of patients, highlighting that cerebellar ataxia is among the diverse neurologic manifestations associated with autoimmune conditions involving these antibodies.

Anti-NMDA R ataxia. The association of cerebellar ataxia with anti-NMDA antibody is very rare. An anti-NMDA antibody-positive 3-year-old boy with chronic cerebellar ataxia and atonic seizures was reported (43). Another young adult patient with teratoma-related opsoclonus-myoclonus syndrome was subsequently reported (63).

Anti-Gluk2 ataxia. Antibodies against the glutamate kainate receptor subunit 2 (GluK2) have been described in eight patients with predominant cerebellar manifestations. The neurologic symptoms had a subacute progression (< 6 weeks). Four patients with a median age of 19 years presented with prominent clinical manifestations compatible with cerebellitis, including opsoclonus in one and two who developed obstructive hydrocephalus (38). Four older patients developed a more diffuse encephalitis, with limb or gait ataxia in two. MRI studies available in seven patients showed multifocal T2-fluid-attenuated inversion recovery (FLAIR) abnormalities in the cerebellum in four. All patients had CSF pleocytosis. Three of the seven patients who received immunotherapy had partial or full recovery. An active tumor (one relapsing Hodgkin lymphoma and one ovarian teratoma) was diagnosed in two patients.

Anti-mGluR1 ataxia. The main neurologic manifestations are subacute cerebellar gait and limb ataxia, sometimes associated with extracerebellar symptoms, such as behavioral changes (irritability, apathy, mood, personality change, psychosis with hallucinations, and catatonia), cognitive changes (memory problems, executive functions, and spatial orientation deficits), or dysgeusia. Seizures are uncommon. MRI at onset mostly shows normal or abnormal findings, such as T2/FLAIR hyperintensities or leptomeningeal gadolinium enhancement in a few patients. However, as the disease progresses, patients show cerebellar atrophy on MRI. Notably, 40% of the patients showed significant improvements or complete resolution of symptoms to immunotherapies including IVIg, steroids, mycophenolate mofetil, cyclophosphamide, and rituximab alone or in combinations (60).

Anti-Homer3 Ab-associated CA. A clinical review of 16 patients with anti-Homer-3 Ab-associated cerebellar ataxia revealed that the condition frequently manifests without identifiable immune triggers. In particular, paraneoplastic associations are rare, with malignancies documented in only two cases (59). MRI findings demonstrated cerebellar atrophy in 56.3% of patients, including 18.8% who exhibited concomitant pontine atrophy and the "hot cross bun" sign. Consequently, anti-Homer-3 Ab-associated cerebellar ataxia should be considered in the differential diagnosis of the cerebellar type of multiple system atrophy (MSA-C). Key features for differentiation include: (1) a broad age of onset (median 50 years; range 10 to 84 years), spanning pediatric to geriatric populations; (2) a high prevalence of neuropsychiatric symptoms (56.3%), including cognitive impairment, seizure, and delirium; (3) inflammatory cerebrospinal fluid profiles; and (4) transient cerebellar MRI signal abnormalities (25.0%). Thus, anti-Homer-3 Ab-associated cerebellar ataxia may be underdiagnosed or misdiagnosed (07).

Anti-glycine R ataxia. Autoantibodies toward GlyR were first reported in 2008 in a single patient with progressive encephalomyelitis, rigidity, and myoclonus (PERM). In a subsequent systematic study of 45 patients with anti-glycine R Ab, limb and gait ataxias were identified in 13% of the patients (04). Patients with anti-glycine R Ab-associated disease generally show a good response to immunotherapy, including different combinations of intravenous methylprednisolone, oral prednisone, IVIg, and plasma exchange.

Anti-myelin-associated glycoprotein (MAG) ataxia. In the CNS, MAG plays a role in the maintenance of myelin integrity and inhibition of the regeneration of cerebellar neurons. Cerebellar ataxia associated with anti-MAG Ab was described in five patients (64). All patients had IgM gammopathy, and four of the five showed clinically evident neuropathy. One patient showed chronic cerebellar ataxia alone (64). Anti-MAG ataxia responds well to rituximab, and such a response is associated with improvement in MR spectroscopy (64).

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Autoimmune GFAP astrocytopathy is the main intermediate filament in mature astrocytes and a component of their cytoskeleton. Autoimmune GFAP astrocytopathy is often associated with other autoimmune diseases, such as type 1 diabetes, thyroiditis, or even other types of autoimmune encephalitis (NMDA encephalitis) (37). Autoimmune GFAP astrocytopathy is characterized by fever, headache, convulsions, delirium, meningism, loss of visual acuity, and ataxia (37). Cerebellar ataxia was described as accompanying meningoencephalomyelitis (40%). Atypical patients with progressive cerebellar ataxia, proximal myoclonus, and bulbar symptomatology have also been reported. CSF studies showed inflammatory changes (monocytic pleocytosis), high protein, and low glucose levels. Brain and spinal cord MRI studies showed nonspecific findings. Intravenous methylprednisolone is usually effective in acute treatment, although some patients also require additional treatment, such as plasma exchange or IVIg. Maintenance therapy using mycophenolate mofetil, azathioprine, or rituximab is necessary in 20% to 50% of the patients in order to prevent relapse (37).

CLIPPERS. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is characterized by marked perivascular T cell inflammation, mainly in the pons, with compatible perivascular gadolinium enhancement on MRI, which responds to corticosteroids (13).

A review of 56 reported cases showed considerable differences in clinical manifestations (13). The condition mainly affects males (67% of the patients), aged 13 to 86 years (mean age at onset: 52.4 years) (13). The patients show subacute onset of varying initial features related to the brainstem pathology, frequently including pancerebellar ataxias, dysarthria, dysphagia, dysgeusia, oculomotor abnormalities, altered facial sensation, facial nerve palsy, vertigo, pyramidal signs, and sensory disorders. In contrast, fever, loss of consciousness, or meningism are rare. The clinical course seems to be relapsing-remitting in nature. MRI shows characteristic changes that reflect perivascular lymphocyte infiltration in the pons and peripontine lesions. The hallmark feature is multiple "punctate" or "curvilinear" gadolinium-enhancing lesions, resulting in "peppering" of the pons with or without peripontine lesions. CSF examination shows either a normal or mild-to-moderate rise in protein level with a mild increase in white cells.

There are no specific serum or CSF biomarkers for CLIPPERS. MRI-compatible CLIPPERS could also result from various pathologies. Thus, it is uncertain whether CLIPPERS is one etiology or a syndrome of heterogeneous etiologies.

Early intervention with corticosteroids improves outcome (13). It is recommended that the initial treatment with intravenous methylprednisolone be followed by maintenance immunotherapy using the combination of oral prednisolone and corticosteroid-sparing immunosuppressants. Because withdrawal of corticosteroids results in disease exacerbation, long-term maintenance therapy is required (13).

IgG4 disease-related ataxia. IgG4-related disease is characterized by the infiltration of lymphocytes and plasma cells that secrete IgG4, leading to tissue fibrosis and destruction. This disease manifests in various phenotypes, including autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, retroperitoneal fibrosis, interstitial nephritis, and arterial inflammation, which can result in aortitis and large vessel vasculitis. Pachymeningitis is recognized as a neurologic manifestation. It can present with headaches or cranial nerve symptoms. Additionally, the disorder may involve the pituitary gland. Generally, corticosteroids have been found to provide therapeutic benefits.

A patient with ataxia also presenting with frontotemporal lobe dementia was reported (20). The patient did not experience headache but had complications due to inflammation of the kidneys and large vessels. A biopsy from the perinephric tissue confirmed IgG4 disease. MRS revealed a significantly low NAA/Cr area ratio in the vermis, suggesting that the cerebellum could be a target of IgG4-related diseases (20).

Cerebellar ataxia induced by immune checkpoint inhibitors. Immune checkpoint inhibitors are currently used for treating several cancers. However, neurologic complications, including myasthenia, Guillain-Barré syndrome, and encephalitis, have been reported in up to 12% of the patients. A systematic study of immune checkpoint inhibitor-associated cerebellar toxicity revealed that the cerebellar immune-related adverse event (irAE) group was significantly associated with male sex, lung cancer, isolated ataxia, and a better outcome compared with paraneoplastic cerebellar degeneration (11; 10).

Summary of differential diagnosis

In contrast to paraneoplastic immune-mediated cerebellar ataxias, non-paraneoplastic immune-mediated cerebellar ataxias respond well to immunotherapy. In addition, the cerebellum has the capacity for compensation and restoration. Clinicians should not lose this therapeutic window and should provide early treatment during the period when cerebellar reserve exists. Clinicians should keep in mind the motto of "time is cerebellum" (49). When cerebellar ataxias are the sole clinical manifestation, differential diagnosis from degenerative and genetic cerebellar ataxias is important.

Confusing conditions

Nonparaneoplastic immune-mediated cerebellar ataxia is usually characterized by an acute/subacute time course. Thus, clinicians should differentiate from cerebellar stroke, Wernicke encephalopathy, multiple sclerosis, and paraneoplastic cerebellar degeneration.

Although cerebellar stroke typically presents with a sudden onset, some patients do not report an acute onset and visit the hospital only a few days after symptom onset, complaining mainly of dizziness, vertigo, vomiting, or mild instability. Thus, the differential diagnosis of a gradual worsening of symptoms over a period of a few days should also include cerebellar stroke (diagnosed on MR imaging).

Paraneoplastic cerebellar degeneration is sometimes preceded by prodromal clinical symptoms such as nausea, vomiting, and dizziness, resembling a viral infection-related disease. Subsequently, patients show gait ataxia, which is followed by pancerebellar involvement. A definite diagnosis is based on (1) confirmation of the presence of cancer, which develops within 5 years of diagnosis of cerebellar ataxia (in most patients, the cancer will be detected within the first 2 years), or (2) appearance of well-characterized onconeural antibodies. The use of a whole-body PET scan is essential in distinguishing between paraneoplastic and nonparaneoplastic immune ataxias.

On the other hand, when nonparaneoplastic immune-mediated cerebellar ataxia shows a chronic or insidious time course, ethanol-induced cerebellar ataxia, toxin-induced cerebellar syndrome (TOICS), and degenerative cerebellar ataxia should be considered.

After checking for exposure to certain toxic agents, such as ethanol, organic mercury, organic solvents (toluene, thinner), certain medications (phenytoin, lithium, metronidazole), and excluding hypothyroidism, imaging studies will exclude conditions such as Chiari malformation, a tumor, or multiple sclerosis, or they will simply demonstrate cerebellar atrophy. In general, cerebellar atrophy is not specific to a particular etiology and can be seen in all of the ataxias. Further genetic analysis should be conducted for the differential diagnosis of autosomal dominant cerebellar ataxias (ADCAs) and autosomal recessive cerebellar ataxias (ARCAs). One systematic study investigated the seroprevalence of autoimmune autoantibodies in patients with sporadic degenerative cerebellar ataxia (56). This study revealed low seroprevalence and low-titer seropositivity for autoantibodies targeting cerebellar antigens, similar to findings in the cerebellar variant of multiple system atrophy (MSA-C), genetically determined degenerative cerebellar ataxias, and other neurodegenerative disease controls (56). However, distinguishing between MSA-C and autoimmune cerebellar ataxia can be challenging. In cases presenting with pure cerebellar atrophy accompanied by the hot cross bun sign and brainstem atrophy, MSA-C should be strongly considered. However, the hot cross bun sign is not pathognomonic of MSA-C and can be seen in paraneoplastic cerebellar degeneration and some genetic ataxias, particularly SCA2. Therefore, it is crucial to acknowledge that several immunological disorders can also manifest with the hot cross bun sign. Notably, six reported cases have identified autoantibodies against GAD, KLHL-11, Ri, and amphiphysin, all of which demonstrated responsiveness to immunotherapy (12). To ensure comprehensive evaluation, it is recommended to investigate the presence of these antibodies in the cerebrospinal fluid. Finally, it should be noted that MSA-C can progress very rapidly and mimic immune ataxias.

Associated or underlying disorders

The association with other autoimmune diseases, such as thyroiditis, type 1 diabetes mellitus, pernicious anemia, and Sjögren syndrome, is common. The HLA type DQ2 is detected in the majority of patients with gluten ataxia or primary autoimmune cerebellar ataxia.

Diagnostic workup

Clue to diagnosis. Although the etiology is diverse, non-paraneoplastic immune-mediated cerebellar ataxias share common clinical manifestations. The onset of cerebellar ataxias is usually acute/subacute, and it can be chronic or insidious. The presence of other autoimmune disorders in the patient or in first-degree relatives may be relevant. The main ataxic feature is gait ataxia, which hinders standing and steady walking. Other manifestations include variable degrees of limb incoordination, dysarthria, and nystagmus. MRI can be normal or show atrophy mainly in the vermis, depending on the duration of the disease. Pleocytosis or oligoclonal bands are sometimes observed in the CSF (47). Studies have highlighted the potential usefulness of MR spectroscopy as a sensitive biological marker of the response to treatment in patients with cerebellar ataxia (22; 24). The ratio of N-acetylaspartate/creatine area is decreased in patients with immune-mediated cerebellar ataxias.

Autoantibodies. Analysis of autoantibodies can be a good tool for the diagnosis of immune-mediated cerebellar ataxias (45; 44; 46; 47; 23; 27) (Table 2).

Table 2. Classification of Autoantibodies in Immune-Mediated Cerebellar Ataxias

Characterized autoantibodies, suggestive of a specific etiology in immune-mediated cerebellar ataxias
Well or partly characterized
Anti-TG2, 6	Gluten ataxia
Anti-PCA-1/Yo	PCD: breast, uterus, and ovarian carcinomas
Anti-ANNA-1/Hu	PCD: small cell lung carcinoma
Anti-Tr/DNER	PCD: Hodgkin lymphoma
Anti-CV2/CRMP5	PCD: small cell lung carcinoma, thymoma
Anti-ANNA-2/Ri	PCD, paraneoplastic opsoclonus myoclonus syndrome: breast carcinoma
Anti-Ma2	PCD: testis and lung carcinomas
Anti-AGNA/SOX1	PCD: small cell lung carcinoma
Anti-amphiphysin	PCD: small cell lung and breast carcinomas
Anti-PCA-2/MAP1B	PCD: small cell lung carcinoma, non-small cell lung carcinoma
Anti-KLHL11	Brainstem/PCD: testicular carcinoma
Autoantibodies found in various neurologic conditions, including cerebellar ataxias, suggestive of autoimmune pathomechanisms
Autoantibodies assumed to have pathogenic roles in the development of cerebellar ataxias
Ion channels and related proteins
Anti-VGCC (P/Q type)	Dysfunction of Ca channel: anti-VGCC ataxia, PCD, Lambert-Eaton syndrome
Anti-DPPX	Dysfunction of K channel?: anti-DPPX encephalitis, anti-DPPX ataxia
Anti-CASPR2	Dysfunction of K channel?: anti-CASPR2 encephalitis, anti-CASPR2 ataxia
Synaptic adhesion/organizing molecules
Anti-LGI1	Dysfunction of presynaptic K channel and postsynaptic AMPA-R: cognitive impairments, sleep disorder. Cerebellar ataxias are rare.
Anti-IgLON5	Unknown function: sleep disorder, bulbar syndrome, progressive supranuclear palsy–resembling syndrome, cognitive decline. Instability might be attributed to cerebellar dysfunction.
Transmitter receptors
Anti-AMPAR	Decrease of AMPAR: anti-AMPA encephalitis. Cerebellar ataxias are of diverse symptoms.
Anti-NMDAR	Decrease of NMDAR: anti-NMDAR encephalitis. Cerebellar ataxias are rare.
Anti-Gluk2	Reversible internalization of GluK2, <10 patients described mots with prominent ataxia
Anti-mGluR1	Dysfunction of mGluR1: anti-mGluR1 ataxia, PCD
Anti-mGluR2	Dysfunction of mGluR2?: PCD?
Anti-mGluR5	Decrease of mGluR5R: anti-mGluR5 encephalitis. Cerebellar ataxias are of diverse symptoms.
Anti-GABA_AR	Decrease of GABA_AR: anti-GABA_AR encephalitis. Cerebellar ataxias are rare.
Anti-GABA_BR	Unknown function: anti-GABA_BR encephalitis. Cerebellar ataxias are rare.
Anti-glycine R	Decrease of glycine R: progressive encephalomyelitis, rigidity, and myoclonus (PERM). Cerebellar ataxias are of diverse symptoms.
Others
Anti-GAD65 (high titer)	Decrease in GABA release: anti-GAD ataxia, PCD, SPS
Anti-MAG	Although well characterized as pathogenic for neuropathy, the mechanism is uncertain: anti-MAG ataxia.
Autoantibodies reported only in a few CA patients, with less characterized significance in ataxia
Anti-GluRδ	Postinfectious cerebellitis, opsoclonus myoclonus syndrome
Anti-CARP VIII	Mostly reported in a few patients with neoplasm
Anti-TRIM9/67	Mostly reported in a few patients with neoplasm
Anti-PKCy	Mostly reported in a few patients with neoplasm
Anti-ZIC4	Mostly reported in a few patients with neoplasm
Anti-TRIM46	<30 patients reported most of them with cancer
Anti-DACH1	<20 patients reported, approximately 90% with cancer
Anti-neuronal intermediate filament	<20 patients reported, approximately 80% with cancer
Anti-Sj/ITPR-1	<20 patients reported, approximately, 50% with cancer
Anti-Ca/ARHGAP26	<30 patients reported, approximately 40% with cancer
Anti-Homer3	< 20 patients reported, non-paraneoplastic ataxia
Anti-Neurochondrin	20 patients reported, non-paraneoplastic ataxia
Anti-Nb/AP3B2	<20 patients reported, non-paraneoplastic ataxia
Anti-Septin-5	10 patients reported, non-paraneoplastic ataxia
This table shows autoantibodies in paraneoplastic and nonparaneoplastic autoimmune ataxia. In paraneoplastic cerebellar degeneration, this table shows the antibodies classified as “major antibodies in PCD” (51). When these autoantibodies are detected, the risk of cancer complications exceeds 80%. Infrequent other autoantibodies were sorted according to the proportion of paraneoplastic syndromes in a study by Muniz-Castrillo and Honnorat (40). ANNA: antineuronal nuclear antibody; CRMP5: collapsin response-mediator protein-5; DNER: delta/notch-like epidermal growth factor–related receptor; KLHL11: Kelch-like protein 11; MAP1B: microtubule-associated protein 1B; PCA: Purkinje cell antibody; SOX1: sex determining region Y-related high mobility group box 1. Unknown “idiopathic” ataxias might correspond to primary autoimmune cerebellar ataxia. CASPR2: contactin-associated protein-like 2; CARP VIII: carbonic anhydrase-related protein VIII; Ca/ARHGAP26: Ca/Rho GTPase-activating protein 26; DACH1: Dachshund homolog 1; DPPX: dipeptidyl-peptidase-like protein 6; GAD65: glutamic acid decarboxylase 65; GluRδ2: glutamate receptor delta2; LGI1: leucine-rich glioma-inactivated; mGluR: metabotropic glutamate receptor; Nb/AP3B2: Nb/adaptor complex 3 B2; PKCγ: protein kinase C gamma; Sj/ITPR-1: Sj/inositol 1,4,5-trisphosphate receptor-1; TRIM: axon initial segment protein tripartite motif; ZIC4: zinc finger protein of the cerebellum 4.

Management

When autoimmunity is triggered by another condition, priority should be given to the treatment of the underlying condition (for example, a gluten-free diet in gluten ataxia and surgical excision of the neoplasm in paraneoplastic cerebellar degeneration) (45; 44; 46; 47; 23; 27). In such cases, subsequent immunotherapies are only necessary if there is evidence of progression despite removal of the trigger. On the other hand, when autoimmunity is not triggered by any underlying condition, immediate immunotherapies are recommended at an early stage.

Immune-mediated cerebellar ataxia therapy algorithm

(Contributed by Dr. Hiroshi Mitoma.)

Induction immunotherapy is provided first to stabilize cerebellar ataxias, followed by maintenance immunotherapy to prevent relapse (45; 47). Various immunotherapies have been used, ranging from intravenous immunoglobulins, glucocorticosteroids, immunosuppressants (in particular, mycophenolate), plasmapheresis, and rituximab, either alone or in different combinations, and the selection is often based on the etiology. To date, however, there are virtually no large-scale randomized studies involving therapeutic strategies (45; 47).

Studies have highlighted the potential usefulness of MR spectroscopy as a sensitive physiological biomarker of the response to treatment in patients with cerebellar ataxias (23; 27). The ratio NAA/Cr area is decreased in patients with cerebellar ataxias, relative to controls, and increases in those who respond to immunotherapy and exhibit improvement of the autoimmune process.

Outcomes

The therapeutic threshold is best illustrated in gluten-free diet therapy in gluten ataxia (45). In a long-term observational study, we examined the outcome of a gluten-free diet in 371 patients with gluten ataxia, including 74% with mild ataxia (ability to walk unaided), 16% with moderate ataxia (inability to walk without support), and 10% with severe ataxia (wheelchair use) (45). A strict gluten-free diet was applied for 1 year, which was confirmed by various serological tests that confirmed the elimination of gluten sensitivity. Importantly, clinical improvement correlated significantly with the severity of cerebellar atrophy and was evident in patients with mild ataxia. A gluten-free diet halted and stabilized cerebellar ataxias but did not improve clinical symptoms in some patients with severe ataxia.

The pathological process of anti-GAD-ataxia includes a transition from functional disorders to cell death (48; 42). Such a shift could be applied as the basis for restorable and nonrestorable stages. Division of the clinical course into stages leads to the notion of cerebellar reserve, which is defined as the capacity for compensation and restoration from certain damage. The physiological mechanisms of cerebellar reserve rest on specific features of the cerebellum: the presence of various forms of synaptic plasticity and divergent projections of mossy fibers to microzones (ie, redundant afferents in one microzone). Physiologically, predictive controls, a specific function of the cerebellum, is maintained in the early stage of immune-mediated cerebellar ataxias. Thus, the aim of any immunotherapy is to halt the etiology progression during the time when cerebellar reserve is preserved (49; 47).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Hiroshi Mitoma MD PhD

Dr. Mitoma of Tokyo Medical University has no relevant financial relationships to disclose.
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Mario Manto MD PhD

Dr. Manto of University of Mons, Belgium, has no relevant financial relationships to disclose.
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Marios Hadjivassiliou MD

Dr. Hadjivassiliou of Royal Hallamshire Hospital has no relevant financial relationships to disclose.
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Editor

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: 2 to 5 years: postinfectious cerebellitis

45 to 64 years: Gluten ataxia, anti-GAD ataxia
Sex preponderance: Female > male: Gluten ataxia, Anti-GAD ataxia
Heredity: None
Population groups selectively affected: None
Occupation groups selectively affected: None

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Nonparaneoplastic autoimmune cerebellar ataxias

Associated Disorders

Autoimmune disorders (thyroid diseases, type 1 diabetes mellitus, pernicious anemia)
Celiac disease in gluten ataxia

Differential Diagnosis

Gluten ataxia
Postinfectious cerebellitis
Opsoclonus myoclonus syndrome
Anti-GAD ataxia
Primary autoimmune cerebellar ataxia
- Miller Fisher syndrome
- Anti-DPPX ataxia
- Anti-Caspr2 ataxia
- Anti-MAG ataxia
- CLIPPERS

Nonparaneoplastic autoimmune cerebellar ataxias

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Table 1. Clinical Profiles of Common Etiologies of Nonparaneoplastic Immune-Mediated Cerebellar Ataxias

Prevention

Differential diagnosis

Common etiologies in nonparaneoplastic immune-mediated cerebellar ataxias

Rare etiologies in nonparaneoplastic immune-mediated cerebellar ataxias

Summary of differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 2. Classification of Autoantibodies in Immune-Mediated Cerebellar Ataxias

Management

Outcomes

Media

References

Contributors

Authors

Editor

Patient Profile

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