Cerebellar Blood Flow and Gene Expression in Crossed Cerebellar Diaschisis after Transient Middle Cerebral Artery Occlusion in Rats.

Crossed cerebellar diaschisis (CCD) is a state of hypoperfusion and hypometabolism in the contralesional cerebellar hemisphere caused by a supratentorial lesion, but its pathophysiology is not fully understood. We evaluated chronological changes in cerebellar blood flow (CbBF) and gene expressions in the cerebellum using a rat model of transient middle cerebral artery occlusion (MCAO). CbBF was analyzed at two and seven days after MCAO using single photon emission computed tomography (SPECT). DNA microarray analysis and western blotting of the cerebellar cortex were performed and apoptotic cells in the cerebellar cortex were stained. CbBF in the contralesional hemisphere was significantly decreased and this lateral imbalance recovered over one week. Gene set enrichment analysis revealed that a gene set for "oxidative phosphorylation" was significantly upregulated while fourteen other gene sets including "apoptosis", "hypoxia" and "reactive oxygen species" showed a tendency toward upregulation in the contralesional cerebellum. MCAO upregulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the contralesional cerebellar cortex. The number of apoptotic cells increased in the molecular layer of the contralesional cerebellum. Focal cerebral ischemia in our rat MCAO model caused CCD along with enhanced expression of genes related to oxidative stress and apoptosis.

Transcriptomic differences in MSA clinical variants.

BACKGROUND: Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C). OBJECTIVE: To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes. METHODS: We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients. RESULTS: Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies. CONCLUSIONS: In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results.

Intravenous immunoglobulins in an adult case of post-EBV cerebellitis.

Post-Epstein-Barr virus (EBV) cerebellitis is very rare complication of infectious mononucleosis and only a few adult cases are reported in literature. We present a 23-year-old patient who was admitted to the neurology service with worsening ataxia, nystagmus and dysarthria, 1 week after infectious mononucleosis. Imaging and cerebrospinal fluid studies were normal, serum studies revealed acute transaminitis and positive EBV viral capsid IgM and IgG. The patient underwent a 5-day course of intravenous immunoglobulins with rapid resolution of all his symptoms and was safely discharged home. The pathophysiology of post-EBV cerebellitis involves autoreactive antibodies, rather than a direct viral insult. Antineuronal antibodies might be the result of a mimicry between EBV proteins and neuronal antigens or they can be secreted by the EBV-transformed lymphocytes themselves. Many reports stress the benign, self-limiting nature of this syndrome; however, immunotherapy might de facto decrease the severity and duration of illness.

Cerebellar disease associated with anti-glutamic acid decarboxylase antibodies: review.

Several neurological syndromes have been recognized associated to GAD antibodies. Among those disorders, cerebellar ataxia (CA) is one of the most common, along with stiff-person syndrome. Patients with GAD associated CA present with a progressive pancerebellar syndrome, with a subacute or chronic evolution, along with other neurological manifestations such as stiffness, oculomotor dysfunction, epilepsy, and cognitive dysfunction. These symptoms may be preceded by the so-called "brainstem attacks", where manifestations consistent with transient dysfunction of the brainstem may be observed. These patients frequently have extra-neurologic autoimmune manifestations such as diabetes mellitus type 1, polyendocrine autoimmune syndrome, pernicious anemia, vitiligo, etc. A proportion of patients may present with an underlying neoplasia, but the course is less aggressive than in those patients with classical paraneoplastic CA with onconeural antibodies. The diagnosis is based on the present of high serum and CSF titers of GAD antibodies, with intrathecal production of such antibodies. Treatment is aimed to decrease the immunological response with intravenous immunoglobulin, steroids, rituximab and oral immunosuppressive drugs. A subacute presentation and rapid initiation of immunotherapy seem to be the predictors of a favorable clinical response.

Garcinia kola aqueous suspension prevents cerebellar neurodegeneration in long-term diabetic rat - a type 1 diabetes mellitus model.

ETHNOPHARMACOLOGICAL RELEVANCE: The development of compounds able to improve metabolic syndrome and mitigate complications caused by inappropriate glycemic control in type 1 diabetes mellitus is challenging. The medicinal plant with established hypoglycemic properties Garcinia kola Heckel might have the potential to mitigate diabetes mellitus metabolic syndrome and complications. AIM OF THE STUDY: We have investigated the neuroprotective properties of a suspension of G. kola seeds in long-term type 1 diabetes mellitus rat model. MATERIALS AND METHODS: Wistar rats, made diabetic by single injection of streptozotocin were monitored for 8 months. Then, they were administered with distilled water or G. kola oral aqueous suspension daily for 30 days. Body weight and glycemia were determined before and after treatment. After sacrifice, cerebella were dissected out and processed for stereological quantification of Purkinje cells. Histopathological and immunohistochemical analyses of markers of neuroinflammation and neurodegeneration were performed. RESULTS: Purkinje cell counts were significantly increased, and histopathological signs of apoptosis and neuroinflammation decreased, in diabetic animals treated with G. kola compared to diabetic rats given distilled water. Glycemia was also markedly improved and body weight restored to non-diabetic control values, following G. kola treatment. CONCLUSIONS: These results suggest that G. kola treatment improved the general condition of long-term diabetic rats and protected Purkinje cells partly by improving the systemic glycemia and mitigating neuroinflammation.

[Autoantibody-associated autoimmune encephalitis and cerebellitis : Clinical presentation, diagnostic work-up and treatment]. / Autoantikörperassoziierte autoimmune Enzephalitiden und Zerebellitiden : Klinik, Diagnostik und Therapie.

There is no other field of neurology where clinically relevant serological biomarkers have witnessed a surge in importance over the past decade resembling that in autoimmune encephalitis and cerebellitis. A multitude of newly discovered neuronal autoantibodies facilitate early diagnosis, estimation of prognosis, and therapeutic decision-making. However, this has led to growing uncertainty with regard to meaningful patient selection, the appropriate extent of testing, and management of seronegative cases. This review summarizes the essential aspects of the clinical presentation, diagnostic work-up, pathophysiology, and treatment of autoimmune encephalitis and cerebellitis.

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

Investigators have hypothesized a range of subcortical neuropathology in the genesis of bilirubin-induced neurologic dysfunction (BIND). The current review builds on this speculation with a specific focus on the cerebellum and its connections in the development of the subtle neuromotor disabilities of BIND. The focus on the cerebellum derives from the following observations: (i) the cerebellum is vulnerable to bilirubin-induced injury; perhaps the most vulnerable region within the central nervous system; (ii) infants with cerebellar injury exhibit a neuromotor phenotype similar to BIND; and (iii) the cerebellum has extensive bidirectional circuitry projections to motor and non-motor regions of the brainstem and cerebral cortex that impact a variety of neurobehaviors. Future study using advanced magnetic resonance neuroimaging techniques have the potential to shed new insights into bilirubin's effect on neural network topology via both structural and functional brain connectivity measurements.

Fear-related behaviors in Lurcher mutant mice exposed to a predator.

The Lurcher mutant mice are characterized by massive cerebellar cortex degeneration. Besides their motor and cognitive disturbances, they exhibit both exaggerated blood corticosterone (CORT) level surge and behavioral disinhibition when confronted to anxiogenic conditions (i.e. to a potential threat). In this study, we assessed if such physiological and behavioral hyperactivity was also detectable in a fear-eliciting situation (actual threat). For this purpose, the behaviors and CORT level elevations in Lurcher mice were compared with those of littermate controls in the predator exposure test: mice were exposed either to a rat (exposure) or to a brief wave of the experimenter's hand (sham exposure). While the basal CORT concentrations (24 h before testing) were not significantly different between mice of both genotypes, the post-exposure ones were higher in Lurcher than in control mice whatever the condition of the experimental design (exposure or sham exposure). Predator exposure did not provoke significant increase of CORT levels whatever the genotype. On the contrary, our data clearly showed that fear-related behaviors of cerebellar mutants facing a real threat were exacerbated in comparison to those of control mice. These results suggest that the cerebellar cortex not only participates to fear conditioning and anxiety but also actively contributes to the modulation of the innate fear-related behaviors.

Isolated cerebellar variant of adrenoleukodystrophy with a de novo adenosine triphosphate-binding cassette D1 (ABCD1) gene mutation.

X-linked adrenoleukodystrophy (X-ALD) shows a wide range of phenotypic expression, but clinical presentation as an isolated lesion of the cerebellar white matter and dentate nuclei has not been reported. We report an unusual presentation of X-ALD only with an isolated lesion of the cerebellar white matter and dentate nuclei. The proband, a 37-year-old man presented with bladder incontinence, slurred speech, dysmetria in all limbs, difficulties in balancing, and gait ataxia. Brain magnetic resonance imaging showed an isolated signal change of white matter around the dentate nucleus in cerebellum. With high level of very long chain fatty acid, gene study showed a de novo mutation in exon 1 at nucleotide position c.277_296dup20 (p.Ala100Cysfs*10) of the adenosine triphosphate-binding cassette D1 gene. It is advised to consider X-ALD as a differential diagnosis in patients with isolated cerebellar degeneration symptoms.

A new cholesterol biosynthesis and absorption disorder associated with epilepsy, hypogonadism, and cerebro-cerebello-bulbar degeneration.

BACKGROUND: Cholesterol is one of the main components of human cell membranes and constitutes an essential substance in the central nervous system, endocrine system, and its hormones, including sex hormones. PATIENT: A 19-year-old male patient presented with failure to thrive, psychomotor deterioration, intractable epilepsy, hypogonadism, and cerebro-cerebello-bulbar degeneration. His serum level of cholesterol was low, ranging from 78.7 to 116.5 mg/dL. RESULTS: The serum concentrations of intermediates in the cholesterol biosynthesis pathway, such as 7-dehydrocholesterol, 8-dehydrocholesterol, desmosterol, lathosterol, and dihydrolanosterol, were not increased. In addition, the levels of the urinary cholesterol biosynthesis marker mevalonic acid, the serum cholesterol absorption markers, campesterol and sitosterol, and the serum cholesterol catabolism marker, 7α-hydroxycholesterol, were all low. CONCLUSIONS: A serum biomarker analysis indicated that the patient's basic abnormality differed from that of Smith-Lemli-Opitz syndrome and other known disorders of cholesterol metabolism. Therefore, this individual may have a new metabolic disorder with hypocholesterolemia because of decreased biosynthesis and absorption of cholesterol.

Plasma brain natriuretic peptide is elevated in the acute phase of intracerebral hemorrhage.

Previous reports have shown that plasma brain natriuretic peptide (BNP) levels are increased in patients with subarachnoid hemorrhage and ischemic stroke. We examined BNP in patients with intracerebral hemorrhage (ICH). Between June 2006 and February 2010, we prospectively enrolled consecutive patients with acute ICH within 24 hours of onset. The plasma BNP level was measured twice, on admission and 4 weeks after onset or at discharge. We investigated whether plasma BNP was elevated in the acute phase of ICH and associated factors. The mean ± standard deviation (SD) plasma BNP level of all patients was 71.1 ± 104.1 pg/mL. The log BNP level positively correlated with the cardio-thoracic ratio (r=0.240, p=0.0001). Moreover, BNP was significantly associated with intraventricular extension (p=0.0039) and hydrocephalus (p=0.0046). The mean ± SD BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhages. In 185 patients, BNP was measured in the subacute phase of ICH. The BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH (69.3 ± 108.1 versus 21.7 ± 23.5 pg/mL, p<0.0001). In conclusion, plasma BNP appears to be elevated in the acute phase of ICH, particularly in those with cerebellar lesions.

Elevated titers of anti-thyroperoxidase antibodies in patients with multiple system atrophy: a pilot study.

OBJECTIVES: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by progressive neuronal loss and alpha-synuclein deposition in oligodendroglial cells in the central nervous system. The cause of MSA remains essentially unknown. A cerebellar syndrome was associated with autoimmune thyroid disease in some cases, apparently not related to MSA and was partially responsive to immunomodulatory therapy. PATIENTS AND METHODS: 28 euthyroid patients who fulfilled the diagnostic criteria for probable MSA, 11 with MSA-cerebellar type (MSA-C), 17 with MSA-parkinsonian type (MSA-P), 28 patients with Parkinson's disease (PD) and 26 normal euthyroid controls were tested the for serum levels of anti-thyroperoxidase antibodies (anti-TPO) and anti-thyroglobulin (Anti-TG) antibodies (Ab). RESULTS: The laboratory results were statistically similar in all three groups, but 3 MSA-C patients had highly elevated anti-TPO Ab titers. CONCLUSION: We identified the presence of elevated anti-TPO levels in a small subgroup of MSA-C patients but neither in MSA-P or PD patients nor in healthy controls. These findings may suggest an autoimmune etiology in some cases of MSA-C.

NGAL as an early biomarker of kidney disease in Joubert syndrome: three brothers compared.

Joubert syndrome (JBTS) is a rare autosomal recessive disorder with an underestimated prevalence due to lack of recognition of clinical signs or failure to diagnose this pathology. JBTS is clinically heterogeneous, and it is characterized by a multiple organ involvement predominantly due to the requirement for Joubert gene function in several tissues. Renal disease affects approximately 30% of patients with JBTS, presenting itself in most cases as nephronophthisis (NPHP), a structural tubulo-interstitial disorder characterized by thickened basal membrane of the tubular epithelium and progressive interstitial fibrosis, associated with cysts at the cortico-medullary junction. We propose three cases concerning three patients with JBTS having different years of illness and degrees of renal impairment, evaluating the parameters of renal function at the time of genetic diagnosis and seen after a follow-up of 7 years. We measured neutrophil gelatinase-associated lipocalin (NGAL), considered as an excellent predictor of kidney injury, to evaluate whether this biomarker might be an early biomarker for JBTS-related kidney disease. NGAL was high in all three cases, but with different levels, indicating a tubular suffering typical of this syndrome, with dissimilar severity in the analyzed subjects. NGAL could represent an early indicator of renal damage useful to start an intensive nephrologic follow-up.

Hyperglycemia as a predictor of poor outcome at discharge in patients with acute spontaneous cerebellar hemorrhage.

Acute stroke patients commonly suffer from hyperglycemia. However, the relationship between hyperglycemia and poor outcome after discharge of patients with acute cerebellar hemorrhage (CH) had not been hitherto investigated.Sixty-two patients with acute spontaneous CH were retrospectively analyzed. The consciousness level, blood glucose/sugar (BS) on arrival and maximum diameter of hematoma, etc., were obtained. Patient prognosis was scored by the Glasgow Outcome Scale (GOS) at discharge and we divided them into good outcome (GOS score of 4 or 5) and poor outcome (GOS score of 1 or 2 or 3) groups. The association between early outcome and clinical characteristics were investigated by multivariate logistic regression. There were 33 (53.4%) patients in the poor outcome group and 29(46.6%) in the good outcome group. The initial BS was significantly higher in the poor outcome group (186.4±57 mg/dl) compared with good outcome group (136.6±31.1 mg/dl)(p<0.001). BS≥140 mg/dl (OR=25.217, p=0.008) and maximum diameter of hematoma ≥3 cm (OR=216.422, p<0.001) were independently correlated with poor outcome. We report the first study that hyperglycemia (BS≥140 mg/dl) on arrival and maximum diameter of hematoma ≥3 cm were found to be strong predictive factors of poor outcome at discharge in patients with acute spontaneous CH.

Alcohol consumption and handwriting: a kinematic analysis.

Cerebellar dysfunction is associated with deficits in the control of movement extent, as well as changes in the amplitude and relative amounts of acceleration and deceleration and action tremor. The present study sought to identify whether cerebellar symptoms occur in the handwriting of intoxicated individuals. Twenty participants in two sub-groups (alcohol dependent and non-alcohol dependent) were asked to write four cursive letter 'l's on a Wacom SD420 graphics tablet before and after consumption of a dose of vodka and orange producing a peak blood alcohol concentration of 0.048%. There was a relationship between blood alcohol concentration and stroke length. Kinematic analysis of handwriting indicated increases in the relative proportions of time spent in acceleration and increases in spectral power around 4Hz. It was found that alcohol intoxication causes symptoms of cerebellar dysfunction, and that alcohol dependent individuals had less ballistic handwriting compared to non-alcohol dependent participants.

Detection of herpesvirus-6A in a case of subacute cerebellitis and myoclonic dystonia.

This is a case study of a child who developed roseola infantum first, then varicella, and was later affected by acute cerebellar syndrome, severe truncal ataxia, and myoclonic dystonia. Human herpesvirus 6 (HHV-6) A and B were detected in the cerebrospinal fluid (CSF) and peripheral blood, respectively, upon ataxia onset. The intricacy of this case suggests multifaceted conclusions ranging from the need for a multidirectional approach to neurological diseases, to confirmation of a more pronounced neurotropism of HHV-6A and a possible role of viruses in myoclonic dystonia syndrome, although this last hypothesis should be confirmed by larger studies.