Advances in cerebellar disorders: pre-clinical models, therapeutic targets, and challenges.

INTRODUCTION: Cerebellar ataxias (CAs) represent neurological disorders with multiple etiologies and a high phenotypic variability. Despite progress in the understanding of pathogenesis, few therapies are available so far. Closing the loop between preclinical studies and therapeutic trials is important, given the impact of CAs upon patients' health and the roles of the cerebellum in multiple domains. Because of a rapid advance in research on CAs, it is necessary to summarize the main findings and discuss future directions. AREAS COVERED: We focus our discussion on preclinical models, cerebellar reserve, the therapeutic management of CAs, and suitable surrogate markers. We searched Web of Science and PubMed using keywords relevant to cerebellar diseases, therapy, and preclinical models. EXPERT OPINION: There are many symptomatic and/or disease-modifying therapeutic approaches under investigation. For therapy development, preclinical studies, standardization of disease evaluation, safety assessment, and demonstration of clinical improvements are essential. Stage of the disease and the level of the cerebellar reserve determine the goals of the therapy. Deficits in multiple categories and heterogeneity of CAs may require disease-, stage-, and symptom-specific therapies. More research is needed to clarify how therapies targeting the cerebellum influence both basal ganglia and the cerebral cortex, poorly explored domains in CAs.

Cerebellar Contributions to Motor Impairments in People with Multiple Sclerosis.

Although Charcot characterized classic cerebellar symptoms in people with multiple sclerosis (PwMS) in 1877, the impact of cerebellar dysfunction on MS symptoms has predominately been evaluated in the last two decades. Recent studies have clearly demonstrated the association between cerebellar pathology, including atrophy and reduced fractional anisotropy in the peduncles, and motor impairments, such as reduced gait velocity and time to complete walking tasks. However, future studies using novel imaging techniques are needed to elucidate all potential pathophysiology that is associated with disability in PwMS. Additionally, future studies are required to determine the most effective treatments for motor impairments in PwMS, including the specific type and duration of exercise interventions, and potential means to amplify their effects, such as transcranial direct current stimulation (tDCS). This mini-review critically discusses the distinct role of cerebellar dysfunction in motor impairments in PwMS, potential treatments, and directions for future studies.

Emotional disorders and the cerebellum: Neurobiological substrates, neuropsychiatry, and therapeutic implications.

The notion that the cerebellum is devoted exclusively to motor control has been replaced by a more sophisticated understanding of its role in neurological function, one that includes cognition and emotion. Early clinical reports, as well as physiological and behavioral studies in animal models, raised the possibility of a nonmotor role for the cerebellum. Anatomical studies demonstrate cerebellar connectivity with the distributed neural circuits linked with autonomic, sensorimotor, vestibular, associative, and limbic/paralimbic brain areas. Identification of the cerebellar cognitive affective syndrome in adults and children underscored the clinical relevance of the role of the cerebellum in cognition and emotion. It opened new avenues of investigation into higher-order deficits that accompany the ataxias and other cerebellar diseases, as well as the contribution of cerebellar dysfunction to neuropsychiatric and neurocognitive disorders. Brain imaging studies have demonstrated the complexity of cerebellar functional topography, revealing a double representation of the sensorimotor cerebellum in the anterior lobe and lobule VIII and a triple cognitive representation in the cerebellar posterior lobe, as well as representation in the cerebellum of the intrinsic connectivity networks identified in the cerebral hemispheres. This paradigm shift in thinking about the cerebellum has been advanced by the theories of dysmetria of thought and the universal cerebellar transform, harmonizing the dual anatomic realities of homogeneously repeating cerebellar cortical microcircuitry set against the heterogeneous and topographically arranged cerebellar connections with extracerebellar structures. This new appreciation of cerebellar incorporation into circuits that subserve cognition and emotion mandates a deeper understanding of the cerebellum by practitioners in behavioral neurology and neuropsychiatry because it impacts the understanding and diagnosis of disorders of emotion and intellect and has potential for novel cerebellar-based approaches to therapy.

Pediatric Fulminant Cerebellitis Is Still a Fatal Disease that We Know Little About! Two Case Reports and a Literature Review.

BACKGROUND Acute cerebellitis is a rare inflammatory disease with a variable clinical course that ranges from self-limiting illness with a benign outcome to a fulminant process (known as fulminant cerebellitis) associated with high risk of morbidity and mortality. It poses a unique challenge to the pediatric community due to its infrequent occurrence and variable presentation, which ultimately contribute to variation in treatment and variation in clinical outcome. This condition has received little attention, with scattered case reports and reviews in the literature and no clear consensus or guidelines for pediatricians to standardize the approach and management. CASE REPORT We report the cases of 2 previously healthy children diagnosed with fulminant cerebellitis. The clinical picture started with severe headache, irritability, and acute deterioration of consciousness level with the absence of cerebellar signs. There was radiological evidence of obstructive hydrocephalus and cerebellar tonsillar herniation in the context of the inflamed cerebellum. The 2 patients received timely standard medical and surgical management for acute cerebellitis in the form of neuroprotective measures, osmotherapy, broad-spectrum antibiotics, and CSF diversion. One patient received aggressive immunomodulatory therapy and had a better outcome compared with the other patient who received no immunomodulatory therapy and had a poor outcome. CONCLUSIONS A high index suspicion and early aggressive intervention are the best tools for achieving optimal outcomes in fulminant cerebellitis in children, given the lack of classic cerebellar signs. In addition to CSF diversion and broad-spectrum antibiotics and antivirals, some patients may benefit from early immunomodulator therapy and posterior fossa decompressive craniotomy.

Infant Fistula-Type Arteriovenous Malformation with Cerebellar Hemorrhage Developed into Nidus-Type in Adolescence.

BACKGROUND: Although arteriovenous malformation (AVM) has been considered to be a congenital vascular malformation, morphologic differences associated with age have been indicated in the literature. CASE DESCRIPTION: We report a case of infant fistula-type AVM that developed into a nidus-type AVM 15 years later. This is the first report to document morphologic changes of AVM over time in 1 case. CONCLUSIONS: The present case suggests the possibly that AVM morphology may change with age and is an important when considering the history of AVM.

The role of the cerebellum in degenerative ataxias and essential tremor: Insights from noninvasive modulation of cerebellar activity.

Over the last three decades, measuring and modulating cerebellar activity and its connectivity with other brain regions has become an emerging research topic in clinical neuroscience. The most important connection is the cerebellothalamocortical pathway, which can be functionally interrogated using a paired-pulse transcranial magnetic stimulation paradigm. Cerebellar brain inhibition reflects the magnitude of suppression of motor cortex excitability after stimulating the contralateral cerebellar hemisphere and therefore represents a neurophysiological marker of the integrity of the efferent cerebellar tract. Observations that cerebellar noninvasive stimulation techniques enhanced performance of certain motor and cognitive tasks in healthy individuals have inspired attempts to modulate cerebellar activity and connectivity in patients with cerebellar diseases in order to achieve clinical benefit. We here comprehensively explore the therapeutic potential of these techniques in two movement disorders characterized by prominent cerebellar involvement, namely the degenerative ataxias and essential tremor. The article aims to illustrate the (patho)physiological insights obtained from these studies and how these translate into clinical practice, where possible by addressing the association with cerebellar brain inhibition. Finally, possible explanations for some discordant interstudy findings, shortcomings in our current understanding, and recommendations for future research will be provided. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Haematoma evacuation in cerebellar intracerebral haemorrhage: systematic review.

BACKGROUND: Guidelines regarding recommendations for surgical treatment of spontaneous cerebellar intracerebral haemorrhage (ICH) differ. We aimed to systematically review the literature to assess treatment strategies and outcomes. METHODS: We searched PubMed and Embase between 1970 and 2019 for randomised or otherwise controlled studies and observational cohort studies. We included studies according to predefined selection criteria and assessed their quality according to the Newcastle-Ottawa Scale (NOS) and risk of bias according to a predefined scale. We assessed case fatality and functional outcome in patients treated conservatively or with haematoma evacuation. Favourable functional outcome was defined as a modified Rankin Scale score of 0-2 or a Glasgow Outcome Scale score of 4-5. RESULTS: We included 41 observational cohort studies describing 2062 patients (40% female) with spontaneous cerebellar ICH. A total of 1171 patients (57%) underwent haematoma evacuation. Ten studies described a cohort of surgically treated patients (n=533) and 31 cohorts with both surgically and conservatively treated patients (n=638 and n=891, respectively). There were no randomised clinical trials nor studies comparing outcome between the groups after adjustment for differences in baseline characteristics. The median NOS score (IQR) was 5 (4-6) out of 8 points and the bias score was 2 (1-3) out of 8, indicative of high risk of bias. Case fatality at discharge was 21% (95% CI 17% to 25%) after conservative treatment and 24% (95% CI 19% to 29%) after haematoma evacuation. At ≥6 months after conservative treatment, case fatality was 30% (95% CI 25% to 30%) and favourable functional outcome was 45% (95% CI 40% to 50%) and after haematoma evacuation, case fatality was 34% (95% CI 30% to 38%) and 42% (95% CI 37% to 47%). CONCLUSIONS: Controlled studies on the effect of neurosurgical treatment in patients with spontaneous cerebellar ICH are lacking, and the risk of bias in published series is high. Due to substantial differences in patient characteristics between conservatively and surgically treated patients, and high variability in treatment indications, a meaningful comparison in outcomes could not be made. There is no good published evidence to support treatment recommendations and controlled, preferably randomised studies are warranted in order to formulate evidence-based treatment guidelines for patients with cerebellar ICH.

Cerebellar Dizziness and Vertigo: Etiologies, Diagnostic Assessment, and Treatment.

Cerebellar dizziness and vertigo account for approximately 10% of diagnoses in a tertiary dizziness center. This term summarizes a large group of disorders with chronic (degenerative, hereditary, acquired cerebellar ataxias), recurrent (episodic ataxias), or acute (stroke, inflammation) presentations. Key to the diagnosis is a comprehensive examination of central ocular motor and vestibular function. Patients with cerebellar dizziness and vertigo usually show a pattern of deficits in smooth pursuit, gaze-holding, saccade accuracy, or fixation-suppression of the vestibulo-ocular reflex. Central fixation nystagmus (e.g., downbeat nystagmus), gaze-evoked nystagmus, central positional nystagmus, or head-shaking nystagmus with cross-coupling (i.e., horizontal head shaking causing inappropriate vertical nystagmus) occurs frequently. Overlap syndromes with peripheral vestibular disorders, such as cerebellar ataxia, neuropathy, and vestibular areflexia, exist rarely. Posturography and gait analysis can contribute to diagnostic differentiation, estimation of the risk of falls, as well as quantification of progression and treatment effects. Patients with cerebellar dizziness and vertigo should receive multimodal treatment, including balance training, occupational therapy, and medication.

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure: Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Cerebellar Syndrome Associated with Thyroid Disorders.

Thyroid disorders, including hypothyroidism, hyperthyroidism and Hashimoto encephalopathy, are considered the most common cause of cerebellar dysfunction due to hormonal imbalance. Typically, cerebellar impairment occurs in the course of hypothyroidism and Hashimoto encephalopathy. Information about demographic, clinical and laboratory features of cerebellar disease associated with thyroid disorders is poor. Our review of the literature (1965 to 2018) identified 28 cases associated with hypothyroidism and 37 cases associated with Hashimoto encephalitis. Both patients with hypothyroidism and Hashimoto encephalopathy presented with signs of ataxia that were similarly distributed in the two groups and were mostly predictive of vermis involvement and frequent impairment of cerebellar hemispheres. Additional neurological signs, like dystonia, psychiatric symptoms, ocular disturbances and myoclonus, could be found in the Hashimoto encephalopathy group alone. When present, atrophy of vermis and often of both cerebellar hemispheres was the main imaging abnormality in both hypothyroidism and Hashimoto encephalopathy. Anti-thyroid antibodies could be detected in three quarters of patients with hypothyroidism and in all patients with Hashimoto encephalopathy. In the patients with hypothyroidism, thyroid replacement therapy yielded complete or partial remission of ataxia. In the Hashimoto encephalopathy group, immunosuppressive treatment provided complete remission of ataxia in about 60% of patients, partial remission in the remaining cases. Owing to the treatable nature of the condition and the high prevalence of thyroid disease among general population, cerebellar syndrome associated with thyroid disorders should be considered an important clinical entity. Information from this review will hopefully stimulate and strengthen awareness of thyroid-associated ataxia among clinicians.

Embryonic Cerebellar Graft Morphology Differs in Two Mouse Models of Cerebellar Degeneration.

Cerebellar diseases causing substantial cell loss often lead to severe functional deficits and restoration of cerebellar function is difficult. Neurotransplantation therapy could become a hopeful method, but there are still many limitations and unknown aspects. Studies in a variety of cerebellar mutant mice reflecting heterogeneity of human cerebellar degenerations show promising results as well as new problems and questions to be answered. The aim of this work was to compare the development of embryonic cerebellar grafts in adult B6CBA Lurcher and B6.BR pcd mutant mice and strain-matched healthy wild type mice. Performance in the rotarod test, graft survival, structure, and volume was examined 2 months after the transplantation or sham-operation. The grafts survived in most of the mice of all types. In both B6CBA and B6.BR wild type mice and in pcd mice, colonization of the host's cerebellum was a common finding, while in Lurcher mice, the grafts showed a low tendency to infiltrate the host's cerebellar tissue. There were no significant differences in graft volume between mutant and wild type mice. Nevertheless, B6CBA mice had smaller grafts than their B6.BR counterparts. The transplantation did not improve the performance in the rotarod test. The study showed marked differences in graft integration into the host's cerebellum in two types of cerebellar mutants, suggesting disease-specific factors influencing graft fate.

Short Review: Investigating ARSACS: models for understanding cerebellar degeneration.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells. These cells have an unlimited self-renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC-derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.

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.

Acute cerebellitis in paediatric patients: Our experience. / Cerebelitis aguda en Pediatría: nuestra experiencia.

INTRODUCTION: Acute cerebellitis is a rare inflammatory disease with a highly variable clinical course that ranges from benign self-limiting symptoms to a fulminant presentation associated with a high risk of death due to compression of the posterior fossa, acute hydrocephalus, and intracranial hypertension. METHODS: We reviewed clinical, laboratory, and radiological findings from children diagnosed with acute cerebellitis between May 2007 and November 2016. We analysed treatments and clinical and radiological progression. RESULTS: Nine children met the diagnostic criteria for cerebellitis. Headache, vomiting, and drowsiness were the most frequent initial symptoms; ataxia, dysarthria, and dysmetria were the most common cerebellar signs. Cerebellitis was diagnosed with magnetic resonance imaging, which revealed cerebellar involvement (unilateral or bilateral); computerised tomography images either were normal or showed indirect signs such as triventricular hydrocephalus due to extrinsic compression of the aqueduct of Sylvius. Corticosteroids were the most commonly used treatment (6 patients). One patient required surgery due to triventricular hydrocephalus. Eight patients recovered completely, whereas the ninth displayed neurological sequelae. CONCLUSIONS: Cerebellitis is a medical and surgical emergency; diagnosis requires a high level of suspicion and an emergency brain magnetic resonance imaging study. It is a clinical-radiological syndrome characterised by acute or subacute encephalopathy with intracranial hypertension and cerebellar syndrome associated with T2-weighted and FLAIR hyperintensities in the cerebellar cortex (unilaterally or bilaterally) and possible triventricular dilatation. Treatment is based on high-dose corticosteroids and may require external ventricular drain placement and decompressive surgery.

Multiple aneurysms on the subarcuate artery arising from the anterior inferior cerebellar artery in a patient with a Borden type I transverse-sigmoid dural arteriovenous fistula manifesting as subarachnoid hemorrhage: A case report.

BACKGROUND: Peripheral anterior inferior cerebellar artery (AICA) aneurysms are rare and commonly associated with vascular malformations, such as cerebellar arteriovenous malformations (AVMs). We present a case wherein multiple AICA feeding aneurysms on the subarcuate artery as a feeding artery of a Borden type I transverse-sigmoid dural arteriovenous fistula (dAVF) manifested as subarachnoid hemorrhage. CASE DESCRIPTION: A 67-year-old woman presented with acute severe headache. Brain computed tomography (CT) demonstrated subarachnoid hemorrhage mainly in the posterior fossa. A transverse-sigmoid dAVF was detected on magnetic resonance angiography (MRA) and three-dimensional-CT angiography (3D-CTA), with no cortical venous reflex. The patient underwent conventional angiography, which showed multiple aneurysms on a small branch of the AICA, feeding a transverse-sigmoid dAVF (Borden type I). The AICA aneurysms seemed flow dependent and ruptured owing to high-flow arteriovenous shunts through the dAVF. Based on the source images of the MRA, the small artery arising from the AICA was considered the subarcuate artery, and it was confirmed on 3D-CTA after the artery was successfully embolized with Onyx without any complications. Multiple aneurysms on the subarcuate artery are extremely rare, and the artery has not been identified as a feeding artery of the transverse-sigmoid dAVF. CONCLUSION: A rare case of multiple ruptured aneurysms on the subarcuate artery was reported in a patient with a Borden type I dAVF at the transverse-sigmoid sinuses manifesting as subarachnoid hemorrhage. Onyx embolization of the parent artery occlusion was feasible and useful in treating this type of feeding artery aneurysm of the AICA with a dAVF.

Zika Virus-Associated Cerebellitis with Complete Clinical Recovery.

Zika virus (ZIKV) was first detected in the Americas in Brazil in 2015, with a rapid spread to surrounding countries. In Panama, the outbreak began in November 2015 in an indigenous community located on the Caribbean side of the country. Zika virus is typically associated with a diffuse rash, fever, and conjunctivitis. It can rarely cause neurologic manifestations, most commonly microcephaly and Guillain-Barré syndrome. Encephalitis and acute encephalomyelitis are known complications, but ZIKV-associated cerebellitis has yet to be reported in the literature. Herein, we report a case of cerebellitis in a patient infected with ZIKV. This patient developed severe frontal headache and vertigo on the third day of illness, and dysarthria and ataxia on the fifth day. After 1 week of hospitalization, the patient completely recovered. The laboratory serological diagnosis was complicated because of the detection of antibodies against dengue, suggesting a secondary flavivirus infection.

Weston-Hurst syndrome with acute hemorrhagic cerebellitis.

Weston-Hurst syndrome is an exceptional variant of ADEM characterized by brain hemorrhages. Lesions are usually supratentorial and death is a usual outcome. We report a cerebellar Weston-Hurst syndrome early treated by craniectomy, steroids and plasma exchange. This is the first case of infratentorial Weston-Hurst syndrome associated with a favorable outcome.

Cerebellar infarction following accidental inhalation of toluene-mixed paint.

We report a case of atypical cerebellar infarction following accidental inhalation of toluene mixed paint. An unconscious 57-year-old housewife with hypertension arrived at our emergency department by ambulance. She had been rescued from a basement (30 m3) 12 h after exposure to paint containing toluene (34%). On arrival, she was comatose (E1V1M1) with a mild fever (37.4 °C). Physical examination showed chemical burns on her buttocks and rales on the left lung. Initial arterial blood gas with 15 L/min of oxygen showed a pH of 7.142, PCO2 of 47.3 mmHg, and PaO2 of 204.7 mmHg. She received endotracheal intubation and mechanical ventilation. Laboratory tests showed elevated white blood cells (26.86 × 109/L), C-reactive protein (0.18 mg/dL), glucose (238 mg/Dl), and CPK (1389 U/L). At 5.5 h after arrival, she became responsive to verbal commands. On day 3, after removal of the endotracheal tube, she began to complain of an occipital headache without neurologic abnormalities. Brain magnetic resonance angiography (MRA) performed on day 6 showed a tiny acute infarction on the right cerebellar hemisphere. We serially measured urinary hippuric acid concentrations (reference range, ≤2.5 g/g creatinine) from 74 h (3.88) after hospital arrival to 218 h (0.5). She was discharged on day 14. Herein we presented a near fatal toluene intoxication (>45,000 mg/m3 estimated based on the basement volume and quantity of paint used) with atypical cerebellar infarction, compared with prior findings of bilateral involvement or reversibility.

Movement disorders in mitochondrial disease: a clinicopathological correlation.

PURPOSE OF REVIEW: The scope of this review is to give an updated account of movement disorders associated with mitochondrial disease, with a particular focus on recently discovered clinicopathological correlations. RECENT FINDINGS: Movement disorders are common clinical manifestations of mitochondrial diseases, in part because of the high vulnerability of neurons controlling motor circuits to mitochondrial respiratory dysfunction and energy failure. Intriguingly, the clinicopathological correlations of movement disorders in mitochondrial disease do not always conform to established neurophysiological knowledge. In particular, nearly complete substantia nigra degeneration and nigrostriatal denervation can occur without being accompanied by any of the clinical signs traditionally associated with parkinsonism. This apparent paradox, may be because of compensation by concomitant impairment of other motor circuits involving the cerebellum and thalamus. SUMMARY: Movement disorders commonly accompany mitochondrial disease and may show paradoxical clinical-anatomical correlations. Further research is warranted in order to elucidate the mechanisms underlying the phenotypic expression of movement disorders in mitochondrial disease. This knowledge will advance our understanding of the pathogenesis of movement disorders in a broader clinical and pathophysiological context.