Immune Ataxias: The Continuum of Latent Ataxia, Primary Ataxia and Clinical Ataxia.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) is now recognized after 3 decades of clinical and experimental research. The cerebellum gathers about 60% of neurons in the brain, is enriched in numerous plasticity mechanisms, and presents a large variety of antigens at the neuroglial level: ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, and glial cells. Cerebellar circuitry is especially vulnerable to immune attacks. After the loss of immune tolerance, IMCAs present in an acute or subacute manner with various combinations of a vestibulocerebellar syndrome (VCS), a cerebellar motor syndrome (CMS), and a cerebellar cognitive affective syndrome/Schmahmann's syndrome (CCAS/SS). IMCAs include gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamic acid decarboxylase (anti-GAD) ataxia, and glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A). In addition, multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen-vascular disorders may also present with cerebellar symptoms when lesions involve cerebellar afferences/efferences. Patients whose clinical profiles do not fit with IMCAs are now gathered in the group of primary autoimmune cerebellar ataxias (PACAs). Latent auto-immune cerebellar ataxia (LACA) refers to a clinical stage with a slow progressive course and a lack of obvious auto-immune background. At a pre-symptomatic stage, patients remain asymptomatic, whereas at the prodromal stage aspecific symptoms occur, announcing the symptomatic neuronal loss. LACA corresponds to a time-window where an intervention could lead to preservation of plasticity mechanisms. Patients may evolve from LACA to PACA and typical IMCAs, highlighting a continuum. Immune ataxias represent a model to elucidate the sequence of events leading to destruction of cerebellar neuronal reserve and develop novel strategies aiming to restore plasticity mechanisms.

Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges-Editorial.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) has been established after 3 decades of clinical and experimental research. The cerebellum is particularly enriched in antigens (ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells) and is vulnerable to immune attacks. IMCAs include various disorders, including gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Other disorders such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen vascular disorders may also present with cerebellar symptoms when lesions are localized to cerebellar pathways. The triggers of autoimmunity are established in GA (gluten sensitivity), PIC and MFS (infections), PCD (malignancy), and OMS (infections or malignant tumors). Patients whose clinical profiles do not match those of classic types of IMCAs are now included in the spectrum of primary autoimmune cerebellar ataxia (PACA). Recent remarkable progress has clarified various characteristics of these etiologies and therapeutic strategies in terms of immunotherapies. However, it still remains to be elucidated as to how immune tolerance is broken, leading to autoimmune insults of the cerebellum, and the consecutive sequence of events occurring during cerebellar damage caused by antibody- or cell-mediated mechanisms. Antibodies may specifically target the cerebellar circuitry and impair synaptic mechanisms (synaptopathies). The present Special Issue aims to illuminate what is solved and what is unsolved in clinical practice and the pathophysiology of IMCAs. Immune ataxias now represent a genuine category of immune insults to the central nervous system (CNS).

Neurophysiology of cerebellar ataxias and gait disorders.

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim of this chapter is to provide an overview of the advances and emerging techniques during these last 2 decades in the neurophysiological tests useful in cerebellar patients for clinical and research purposes. Clinically, patients exhibit various combinations of a vestibulocerebellar syndrome, a cerebellar cognitive affective syndrome and a cerebellar motor syndrome which will be discussed throughout this chapter. Cerebellar patients show abnormal Bereitschaftpotentials (BPs) and mismatch negativity. Cerebellar EEG is now being applied in cerebellar disorders to unravel impaired electrophysiological patterns associated within disorders of the cerebellar cortex. Eyeblink conditioning is significantly impaired in cerebellar disorders: the ability to acquire conditioned eyeblink responses is reduced in hereditary ataxias, in cerebellar stroke and after tumor surgery of the cerebellum. Furthermore, impaired eyeblink conditioning is an early marker of cerebellar degenerative disease. General rules of motor control suggest that optimal strategies are needed to execute voluntary movements in the complex environment of daily life. A high degree of adaptability is required for learning procedures underlying motor control as sensorimotor adaptation is essential to perform accurate goal-directed movements. Cerebellar patients show impairments during online visuomotor adaptation tasks. Cerebellum-motor cortex inhibition (CBI) is a neurophysiological biomarker showing an inverse association between cerebellothalamocortical tract integrity and ataxia severity. Ataxic gait is characterized by increased step width, reduced ankle joint range of motion, increased gait variability, lack of intra-limb inter-joint and inter-segmental coordination, impaired foot ground placement and loss of trunk control. Taken together, these techniques provide a neurophysiological framework for a better appraisal of cerebellar disorders.

Paraneoplastic Ataxia: Antibodies at the Forefront Have Become Routine Biomarkers.

Paraneoplastic cerebellopathies are immune-mediated disorders targeting primarily the cerebellar circuitry, often presenting in a subacute course. The syndrome often develops before the cancer. Therefore, its identification often leads secondarily to a diagnosis of cancer, a critical step to stabilize symptoms. Two categories of antibodies have been identified these last 30 years: (a) onconeuronal antibodies which are directed against intracellular antigens, and (b) antibodies which are directed against synaptic and cell surface proteins. These latter impact on the location and function of the antigens, causing a genuine neuronal dysfunction. Appropriate and fast tumor screening has emerged as a recommendation facing a subacute cerebellar syndrome suspected to be paraneoplastic. Search for antibodies is now a milestone for the diagnosis.

Nothnagel Syndrome.

The internist Hermann Nothnagel (1841-1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the involvement of the vermis in the pathophysiology of motor ataxia. Between 1879 and 1889, he reported four cases of tectal tumors that clinically manifested with bilateral ophthalmoplegia and unilateral gait ataxia, culminating in the Cerebellar Classic highlighted here. Nothnagel attributed this clinical syndrome to lesions of the colliculi ("quadrigeminal bodies") and compression of the nuclei of the third cranial nerves, but also left open the possibility of the involvement of neighboring structures, such as the cerebellar vermis. Today, the ataxic component of Nothnagel syndrome is explained by a dorsal midbrain abnormality of either neoplastic or vascular origin, involving the superior cerebellar peduncles, besides the oculomotor nerves.

Rare Etiologies in Immune-Mediated Cerebellar Ataxias: Diagnostic Challenges.

The cerebellum is particularly enriched in antigens and represents a vulnerable target to immune attacks. Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies, such as gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Apart from these well-established entities, cerebellar ataxia (CA) occurs also in association with autoimmunity against ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells, as well as the brainstem antigens. Most of these conditions manifest diverse neurological clinical features, with CAs being one of the main clinical phenotypes. The term primary autoimmune cerebellar ataxia (PACA) refers to ataxic conditions suspected to be autoimmune even in the absence of specific well-characterized pathogenic antibody markers. We review advances in the field of IMCAs and propose a clinical approach for the understanding and diagnosis of IMCAs, focusing on rare etiologies which are likely underdiagnosed. The frontiers of PACA are discussed. The identification of rare immune ataxias is of importance since they are potentially treatable and may lead to a severe clinical syndrome in absence of early therapy.

Cerebellar Ataxia With Anti-DNER Antibodies: Outcomes and Immunologic Features.

BACKGROUND AND OBJECTIVES: There is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor-related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies. METHODS: Patients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface. RESULTS: Twenty-eight patients were included (median age, 52 years, range 19-81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3-238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro. DISCUSSION: DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell-targeting treatments.

The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.

From Cerebellar Apoplexy in 1849 to Cerebellar Stroke in the 2020s: Robert Dunn's Contribution.

Stroke of the cerebellum represents about 10% of strokes of the brain. Both infarction and hemorrhage manifest with symptoms related to the location and extent of the lesion(s). Bilateral cerebellar infarcts constitute up to one third of all cerebellar infarctions. The leading cause of cerebellar infarcts is emboli of cardiac origin or from intra-arterial sources. Potential complications include brainstem compression and hydrocephalus. Malignant cerebellar edema is a life-threatening complication of ischemic posterior circulation stroke requiring urgent management. The advent of MRI has revolutionized the early diagnosis in vivo, showing small and large territorial infarcts, hemorrhages, and venous infarcts. Endovascular procedures are growingly applied and are impacting on the prognosis of stroke, although cerebellar stroke from occlusion of small cerebellar arteries is currently not accessible to thrombectomy. Surgical procedures of space-occupying stroke include external ventricular drainage, suboccipital craniotomy, or combined procedures. In 1849, Robert Dunn (1799-1877), an English surgeon, reported the details of a case of apoplexy of the cerebellum in a 52-year-old man, pointing to the importance of post-mortem studies of patients followed meticulously during lifetime. Dunn discussed inflammation surrounding hemorrhage as a source of cerebral degeneration, linking for the first time cerebellar stroke, neuroinflammation, and atherosclerosis.

Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms.

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.

Cerebellar long-term depression and auto-immune target of auto-antibodies: the concept of LTDpathies.

There is general agreement that auto-antibodies against ion channels and synaptic machinery proteins can induce limbic encephalitis. In immune-mediated cerebellar ataxias (IMCAs), various synaptic proteins, such as GAD65, voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) are auto-immune targets. Among them, the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies remain unclear. Despite divergent auto-immune and clinical profiles, these subtypes show common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome. The favorable prognosis reflects functional cerebellar disorders without neuronal death. Interestingly, these autoantigens are all involved in molecular cascades for induction of long-term depression (LTD) of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a crucial mechanism of synaptic plasticity in the cerebellum. We suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF-PC LTD, which results in impairment of restoration or maintenance of the internal model and triggers cerebellar ataxias. The novel concept of LTDpathies could lead to improvements in clinical management and treatment of cerebellar patients who show these antibodies.

CSF HIV RNA Escape in Opsoclonus-Myoclonus-Ataxia Syndrome: Case Report and Review of the Literature.

Background: Human immunodeficiency viruses (HIV) infection is associated with a broad range of neurological manifestations, including opsoclonus-myoclonus ataxia syndrome (OMAS) occurring in primary infection, immune reconstitution syndrome or in case of opportunistic co-infection. Case: We report the exceptional case of a 43-year-old female under HIV treatment for 10 years who presented initially with suspected epileptic seizure. Although the clinical picture slightly improved under anti-epileptic treatment, it was rapidly attributed to OMAS. The patient exhibited marked opsoclonus, mild dysarthria, upper limbs intermittent myoclonus, ataxia in 4 limbs, truncal ataxia, and a severe gait ataxia (SARA score: 34). The diagnostic work-up showed radiological and biological signs of central nervous system (CNS) inflammation and cerebral venous sinus thromboses. The HIV viral load was higher in cerebrospinal fluid (CSF) than in the blood (4,560 copies/ml vs. 76 copies/ml). She was treated for 5 days with pulsed corticotherapy. Dolutegravir and anticoagulation administration were initiated. Follow-ups at 2 and 4 months showed a dramatic improvement of clinical neurologic status (SARA score at 4 months: 1), reduction of CNS inflammation and revealed undetectable CSF and serum viral loads. Conclusion: This case underlines the importance of the evaluation of the CSF viral load in HIV patients developing OMAS and suggests CSF HIV RNA escape as a novel cause for OMAS.

Task Force Paper On Cerebellar Transplantation: Are We Ready to Treat Cerebellar Disorders with Cell Therapy?

Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges.

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.

Delayed Posterior Reversible Leukoencephalopathy Syndrome Triggered by FLOT Chemotherapy.

Posterior reversible encephalopathy syndrome (PRES) is a potentially severe disorder of the autoregulation of cerebral perfusion. The major clinical manifestations are headache, seizures, altered mental status, and visual loss. The typical radiological finding is vasogenic edema predominating in the white matter of occipital and parietal lobes. PRES is increasingly recognized as a clinico-radiological entity owing to improvements and fast availability of brain imaging, especially magnetic resonance imaging (MRI). We present the exceptional case of a 67-year-old female patient with a gastric adenocarcinoma at stage IIB (T3N0M0) treated by FLOT chemotherapy (5-fluorouracil, oxaliplatin, docetaxel, and folinic acid). Two months after the unique administration of FLOT regimen, she developed sudden posterior headache and visual loss. Blood pressure values were normal. Cerebral tomography showed ischemic-like occipital bilateral lesions, and angiographic sequences revealed breakdown of the blood-brain barrier (BBB). MRI revealed bilateral parieto-occipital T1 hypointensity and T2 hyperintensity, which demonstrated vasogenic edema. The rest of the parts of the lesions were T1 hyperintensity, T2 hyperintensity, and diffusion-weighted imaging (DWI) hyperintensity, which indicate cortical laminar necrosis. After injection of gadolinium, a linear enhancement of the cortex was observed. She was treated with oral nimodipine. Follow-up was characterized by permanent visual sequelae and tetraparesis. PRES represents an urgent neurological condition. Our observation highlights that PRES should be considered in patients under chemotherapy, even when their blood pressure remains within normal range. This is the first report of PRES triggered by FLOT chemotherapy and with a silent window of 2 months between chemotherapy and PRES, widening further the spectrum of chemotherapy-induced PRES. Our case highlights the potential role of FLOT regimen in the pathogenesis of PRES and the need for a novel approach in terms of prevention of this potentially fatal complication when patients receive chemotherapy.

Cerebellar motor syndrome from children to the elderly.

More than a century after the description of its cardinal components, the cerebellar motor syndrome (CMS) remains a cornerstone of daily clinical ataxiology, in both children and adults. Anatomically, motor cerebellum involves lobules I-V, VI, and VIII. CMS is typically associated with errors in the metrics of voluntary movements and a lack of coordination. Symptoms and motor signs consist of speech deficits, impairments of limb movements, and abnormalities of posture/gait. Ataxic dysarthria has a typical scanning (explosive with staccato) feature, voice has a nasal character, and speech is slurred. Cerebellar mutism is most common in children and occurs after resection of a large midline cerebellar tumor. Ataxia of limbs includes at various degrees dysmetria (hypermetria: overshoot, hypometria: undershoot), dysdiadochokinesia, cerebellar tremor (action tremor, postural tremor, kinetic tremor, some forms of orthostatic tremor), isometrataxia, disorders of muscle tone (both hypotonia and cerebellar fits), and impaired check and rebound. Handwriting is irregular and some patients exhibit megalographia. Cerebellar patients show an increased body sway with a broad-based stance (ataxia of stance). Gait is irregular and staggering. Delayed learning of complex motor skills may be a prominent feature in children. CMS is currently explained by the inability of the cerebellum to handle feedback signals during slow movements and to create, store, select, and update internal models during fast movements. The cerebellum is embedded in large-scale brain networks and is essential to perform accurate motor predictions related to body dynamics and environmental stimuli. Overall, the observations in children and adults exhibiting a CMS fit with the hypothesis that the cerebellum contains neural representations reproducing the dynamic properties of body, and generates and calibrates sensorimotor predictions. Therapies aiming at a reinforcement or restoration of internal models should be implemented to cancel CMS in cerebellar ataxias. The developmental trajectory of the cerebellum, the immature motor behavior in children, and the networks implicated in CMS need to be taken into account.

Toxic-induced cerebellar syndrome: from the fetal period to the elderly.

The cerebellum is a brain region which is particularly susceptible to intoxication. Clinical presentation is heterogeneous. It is often considered that elderly patients and patients presenting pre-existing structural lesions of the posterior fossa are particularly at risk of developing a toxic-induced cerebellar syndrome (TOICS). However, TOICS may occur at any age, including in utero. Indeed, the cerebellum is highly vulnerable during neurodevelopment. Amongst cerebellotoxic agents, ethanol is the most commonly implicated. The vermis is a privileged target. Ethanol exerts toxic effects upon neurons, glia (especially astrocytes and oligodendrocytes), and myelin sheaths. Prenatal alcohol exposure causes teratogenic effects on the developing cerebellum, impeding neuronal migration and differentiation. In adults, cerebellar ataxia is a major feature of both acute and chronic ethanol intoxication. Wernicke encephalopathy is a medical emergency characterized by a triad of ophthalmoplegia, ataxia, and impaired mental status. It requires the immediate administration of high doses of thiamine by the intravenous route. The following drugs may induce a permanent cerebellar syndrome: phenytoin, lithium salts, antineoplastics, and heroin. In addition to ethanol and drugs, environmental agents are also a source of TOICS. In particular, the cerebellum is susceptible to metal intoxication. The recently described deposits of gadolinium in cerebellar nuclei in patients who had received multiple intravenous administrations are a matter of concern on a worldwide scale but we still lack the demonstration of clinically relevant effects upon motor, oculomotor, or cognitive function. Because cerebellar symptoms may be subtle or immersed in a complex encephalopathy with combined involvement of the peripheral nervous system, the diagnosis of TOICS is often overlooked. The life-threatening risk of edema of the posterior fossa with compression of the brainstem should be kept in mind, including in cases of posterior reversible encephalopathy syndrome, and requires posterior fossa decompression when acute hydrocephalus occurs.

Endocrine disorders and the cerebellum: from neurodevelopmental injury to late-onset ataxia.

Hormonal disorders are a source of cerebellar ataxia in both children and adults. Normal development of the cerebellum is critically dependent on thyroid hormone, which crosses both the blood-brain barrier and the blood-cerebrospinal fluid barrier thanks to specific transporters, including monocarboxylate transporter 8 and the organic anion-transporting polypeptide 1C1. In particular, growth and dendritic arborization of Purkinje neurons, synaptogenesis, and myelination are dependent on thyroid hormone. Disturbances of thyroid hormone may also impact on cerebellar ataxias of other origin, decompensating or aggravating the pre-existing ataxia manifesting with motor ataxia, oculomotor ataxia, and/or Schmahmann syndrome. Parathyroid disorders are associated with a genuine cerebellar syndrome, but symptoms may be subtle. The main conditions combining diabetes and cerebellar ataxia are Friedreich ataxia, ataxia associated with anti-GAD antibodies, autoimmune polyglandular syndromes, aceruloplasminemia, and cerebellar ataxia associated with hypogonadism (especially Holmes ataxia/Boucher-Neuhäuser syndrome). The general workup of cerebellar disorders should include the evaluation of hormonal status, including thyroid-stimulating hormone and free thyroxine levels, and hormonal replacement should be considered depending on the laboratory results. Cerebellar deficits may be reversible in some cases.

GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies.

BACKGROUND: Autoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS). GAD65Ab are also reported in cases of epilepsy, indicating an autoimmune component. GAD65Ab in patients with co-occurring T1D, epilepsy or SPS may be part of either autoimmune pathogenesis. To dissect the etiologies associated with GAD65Ab, we analyzed GAD65Ab titer, epitope specificity and enzyme inhibition in GAD65Ab-positive patients diagnosed with epilepsy (n = 28), patients with epilepsy and T1D (n = 10), patients with SPS (n = 20), and patients with T1D (n = 42). RESULTS: GAD65Ab epitope pattern in epilepsy differed from T1D and SPS patients. Four of 10 patients with co-occurring T1D and epilepsy showed GAD65Ab profiles similar to T1D patients, while lacking GAD65Ab characteristics found in GAD65Ab-positive epilepsy patients. One of these patients responded well to anti-epileptic drugs (AEDs), while another patient did not require medication for seizure control. The third patient was refractory due to a diagnosis of meningioma. The response of the remaining patient to AEDs was unknown. GAD65Ab in the remaining six patients with T1D and epilepsy showed profiles similar to those in epilepsy patients. CONCLUSIONS: Different autoimmune responses associated with T1D, epilepsy and SPS are reflected by disease-specific GAD65Ab patterns. Moreover, the epileptic etiology in patients diagnosed with both T1D and epilepsy may present two different etiologies regarding their epileptic condition. In one group T1D co-occurs with non-autoimmune epilepsy. In the other group GAD65Ab are part of an autoimmune epileptic condition.

Time Is Cerebellum.

The cerebellum characteristically has the capacity to compensate for and restore lost functions. These compensatory/restorative properties are explained by an abundant synaptic plasticity and the convergence of multimodal central and peripheral signals. In addition, extra-cerebellar structures contribute also to the recovery after a cerebellar injury. Clinically, some patients show remarkable improvement of severe ataxic symptoms associated with trauma, stroke, metabolism, or immune-mediated cerebellar ataxia (IMCA, e.g., multiple sclerosis, paraneoplastic cerebellar degeneration, gluten ataxia, anti-GAD65 antibody-associated cerebellar ataxia). However, extension of a cerebellar lesion can impact upon the fourth ventricle or the brainstem, either by direct or indirect mechanisms, leading to serious complications. Moreover, cerebellar reserve itself is affected by advanced cell loss and, at some point of disease progression, deficits become irreversible. Such phase transition from a treatable/restorable state (the reserve is still sufficient) to an untreatable state (the reserve is severely affected) is a loss of therapeutic opportunity, highlighting the need for early treatment during the restorable stage. Based on the motto of "Time is Brain," a warning that stresses the importance of early therapeutic intervention in ischemic diseases, we propose "Time is Cerebellum" as a principle in the management of patients with cerebellar diseases, especially immune ataxias whose complexity often delay the therapeutic intervention. Indeed, this concept should not be restricted to ischemic cerebellar diseases. We argue that every effort should be made to reduce the diagnostic delay and to initiate early therapy to avoid the risk of transition from a treatable state to an irreversible condition and an associated accumulation of disability. The myriad of disorders affecting the cerebellum is a challenging factor that may contribute to irreversible disability if the window of therapeutic opportunity is missed.