Enfermedad de Fahr. A propósito de un caso

El síndrome de Fahr, o ferrocalcinosis cerebrovascular, o calcinosis de los núcleos del cerebro, se caracteriza por un depósito anómalo del calcio sin anomalía en el metabolismo del calcio. Se acumula, principalmente, en los ganglios basales, núcleos dentados cerebelosos y sustancia blanca. Es un trastorno neurológico degenerativo asociado a síntomas tales como trastornos del movimiento y síntomas neuropsiquiátricos. Se presenta el caso de un paciente masculino de 65 años de edad, de procedencia rural, viudo, con antecedentes personales de hipertensión arterial, diabetes mellitus tipo 1 y adenoma de próstata, para lo cual lleva tratamiento con Cardicor, Lasix, Plaunac, DuoPlavin y Adenuric. Es llevado a emergencias por la ambulancia presentando convulsiones tónico-clónicas generalizadas sin relajación de esfínter, que respondieron a la administración de diazepam 10 mg endovenoso. Se diagnosticó enfermedad de Fahr. El paciente evolucionó satisfactoriamente y egresó a los cinco días de su ingreso.

Fahr's syndrome, or cerebrovascular ferro-calcinosis, or calcinosis of the nuclei of the brain, is characterized by abnormal calcium deposition without abnormality in calcium metabolism. It accumulates mainly in the basal ganglia, cerebellar dentate nuclei and white matter. It is a degenerative neurological disorder associated with symptoms such as movement disorders and neuropsychiatric symptoms. The case of a 65-year-old male patient, from rural origin, widower, with a personal history of high blood pressure, type 1 diabetes mellitus, and prostate adenoma is presented. For this, he is treated with Cardicor, Lasix, Plaunac, DuoPlavin and Adenuric. He was taken to the emergency room by ambulance presenting generalized tonic-clonic seizures without sphincter relaxation, which responded to the administration of intravenous diazepam 10 mg. Fahr's syndrome was diagnosed, the patient progressed satisfactorily and was discharged 5 days after admission.

Resting-state functional connectivity-based parcellation of the human dentate nucleus: new findings and clinical relevance.

For years, the cerebellum was left out of functional magnetic resonance imaging (fMRI) studies due to technological limitations. The advent of novel data acquisition and reconstruction strategies (e.g., whole-brain simultaneous multi-slice imaging) employing multi-channel array coils has overcome such limitations, ushering unprecedented improvements in temporal signal-to-noise ratio and spatiotemporal resolution. Here, we aim to provide a brief report on the deep cerebellar nuclei, specifically focusing on the dentate nuclei, the primary output nuclei, situated within both cognitive and motor cerebello-cerebral circuits. We highlight the importance of functional parcellation in refining our understanding of broad resting-state functional connectivity (RSFC) in both health and disease. First, we review work relevant to the functional topography of the dentate nuclei, including recent advances in functional parcellation. Next, we review RSFC studies using the dentate nuclei as seed regions of interest in neurological and psychiatric populations and discuss the potential benefits of applying functionally defined subdivisions. Finally, we discuss recent technological advances and underscore ultrahigh-field neuroimaging as a tool to potentiate functionally parcellated RSFC analyses in clinical populations.

Determinant of the cerebellar cognitive affective syndrome in Friedreich's ataxia.

BACKGROUND: Individuals with Friedreich's ataxia (FRDA) display significantly lower performances in many cognitive domains with a pattern of impairment that falls within the cerebellar cognitive affective syndrome (CCAS). OBJECTIVE: To assess in a large cohort of individuals with FRDA, the main determinant of the CCAS using multiple variable regression models. METHODS: This is a monocentric observational study that included 39 individuals with FRDA. Ataxic motor symptoms were evaluated with the SARA and cognitive functions with the CCAS-Scale (CCAS-S). Age, SARA, GAA1, Age of symptoms onset (ASO), Age and disease duration (DD) were chosen as covariates in a linear regression model to predict CCAS-S failed items and covariates in a logistic regression model to predict definite CCAS. RESULTS: Patients mean age, SARA score, ASO, DD and GAA1 were respectively of 29 ± 14, 22 ± 10, 14 ± 11, 15 ± 9 and 712 ± 238 (4 point-mutations). Mean CCAS-S raw score was of 86 ± 16, mean number of failed items was 2.9 ± 1.6. Twenty-three individuals had definite CCAS. The multiple linear regression model with age, SARA, ASO, DD & GAA1 as covariates was statistically significant to predict CCAS-S failed items. The SARA was the only significant coefficient in regression models for predicting CCAS-S failed items number and the definite CCAS occurrence. CONCLUSIONS: CCAS is highly prevalent in adult individuals with FRDA. CCAS is predicted by ataxic motor symptoms severity. This finding supports common core cerebellar pathophysiology in both cognitive and motor symptoms in FRDA and warrants screening for CCAS, especially in patients with SARA > 20.

Metronidazole induced cerebellar toxicity after prolonged treatment of large multiloculated pyogenic liver abscess; A case report and literature review.

Metronidazole is a common antibiotic agent for hepatic abscesses, which require both gram-negative and anaerobic coverage. Rarely, this antibiotic has been found to induce encephalopathy. Here, we describe a 65-year-old male who was treated with metronidazole for his hepatic abscess, who presented with syncope and questionable seizure and was found to have magnetic resonance imaging (MRI) brain findings consistent with metronidazole toxicity. Our patient demonstrated striking brain MRI findings which can be used to further understand the process behind this medication-induced toxicity. Hypotheses of this mechanism include swelling of axons secondary to increased water or vasospasm leading to reversible ischemia that is localized in the brain. In terms of MRI findings, brain lesions tend to populate bilaterally with focus at the dorsal pons, midbrain, cerebellar dentate nuclei (as with our patient), dorsal medulla, or splenium of corpus callosum. Additional research is warranted regarding this rare manifestation and timely removal of the offending agent is crucial for reversal of symptoms.

Big contributions of the little brain for precision psychiatry.

Our previous work using 3T functional Magnetic Resonance Imaging (fMRI) parcellated the human dentate nuclei (DN), the primary output of the cerebellum, to three distinct functional zones each contributing uniquely to default-mode, salience-motor, and visual brain networks. In this perspective piece, we highlight the possibility to target specific functional territories within the cerebellum using non-invasive brain stimulation, potentially leading to the refinement of cerebellar-based therapeutics for precision psychiatry. Significant knowledge gap exists in our functional understanding of cerebellar systems. Intervening early, gauging severity of illness, developing intervention strategies and assessing treatment response, are all dependent on our understanding of the cerebello-cerebral networks underlying the pathology of psychotic disorders. A promising yet under-examined avenue for biomarker discovery is disruptions in cerebellar output circuitry. This is primarily because most 3T MRI studies in the past had to exclude cerebellum from the field of view due to limitations in spatiotemporal resolutions. Using recent technological advances in 7T MRI (e.g., parallel transmit head coils) to identify functional territories of the DN, with a focus on dentato-cerebello-thalamo-cortical (CTC) circuitry can lead to better characterization of brain-behavioral correlations and assessments of co-morbidities. Such an improved mechanistic understanding of psychiatric illnesses can reveal aspects of CTC circuitry that can aid in neuroprognosis, identification of subtypes, and generate testable hypothesis for future studies.

Motor and higher-order functions topography of the human dentate nuclei identified with tractography and clustering methods.

Deep gray matter nuclei are the synaptic relays, responsible to route signals between specific brain areas. Dentate nuclei (DNs) represent the main output channel of the cerebellum and yet are often unexplored especially in humans. We developed a multimodal MRI approach to identify DNs topography on the basis of their connectivity as well as their microstructural features. Based on results, we defined DN parcellations deputed to motor and to higher-order functions in humans in vivo. Whole-brain probabilistic tractography was performed on 25 healthy subjects from the Human Connectome Project to infer DN parcellations based on their connectivity with either the cerebral or the cerebellar cortex, in turn. A third DN atlas was created inputting microstructural diffusion-derived metrics in an unsupervised fuzzy c-means classification algorithm. All analyses were performed in native space, with probability atlas maps generated in standard space. Cerebellar lobule-specific connectivity identified one motor parcellation, accounting for about 30% of the DN volume, and two non-motor parcellations, one cognitive and one sensory, which occupied the remaining volume. The other two approaches provided overlapping results in terms of geometrical distribution with those identified with cerebellar lobule-specific connectivity, although with some differences in volumes. A gender effect was observed with respect to motor areas and higher-order function representations. This is the first study that indicates that more than half of the DN volumes is involved in non-motor functions and that connectivity-based and microstructure-based atlases provide complementary information. These results represent a step-ahead for the interpretation of pathological conditions involving cerebro-cerebellar circuits.

Metronidazole-induced encephalopathy: a systematic review.

BACKGROUND AND AIMS: Metronidazole, a commonly used antibiotic drug, can cause adverse effects in the central nervous system termed metronidazole-induced encephalopathy, leading to diagnostic challenges. The condition is rare and a detailed description of its phenotype is lacking. In this systematic review we investigated the clinical features of metronidazole-induced encephalopathy to promote recognition and elaborate the description. METHODS: We performed a systematic literature search using PubMed.gov and hand searched the reference lists of included articles and other publications of interest. We included case series and single reports describing individual patients developing symptoms from the central nervous system in relation to metronidazole treatment. Data were extracted and analyzed descriptively. RESULTS: We identified 779 publications of which 112 papers comprising 136 patients were included. Typical findings were dysarthria, gait instability, limb dyscoordination and altered mental status. Frequently, patients concomitantly presented with metronidazole-induced polyneuropathy. Liver disease was the most common pre-existing condition. MRI showed a characteristic pattern of reversible symmetrical hyperintense lesions on T2/FLAIR of the dentate nuclei in 90% of patients. Most patients improved significantly after discontinuation of metronidazole. Poor outcome was associated with severe comorbidity. CONCLUSION: Metronidazole-induced encephalopathy should be considered in patients presenting with neurological symptoms in relation to newly initiated or prolonged metronidazole treatment. MRI changes are highly characteristic and specific. Patients with liver disease are at increased risk. Prognosis is good if recognized early.

A case of methylprednisolone treatment for metronidazole-induced encephalopathy.

BACKGROUND: Metronidazole, a common antimicrobial agent, can induce encephalopathy in rare cases. After discontinuing metronidazole, most patients show clinical improvement. However, in the face of deteriorating conditions, there have done not to have reports of effective drug treatment. CASE PRESENTATION: A 57-year-old man was admitted to our hospital due to dysarthria and ataxic gait after taking metronidazole at the dose of about 32 g for 20 days. Neurological examination showed that his upward and outward movements of bilateral eyeballs were limited, and horizontal and vertical nystagmus were noted. The brain magnetic resonance imaging showed hyper-intensities in the bilateral cerebellar dentate nuclei, medulla oblongata, midbrain and red nuclei in T2W and FLAIR images. However, the patient's clinical symptoms worsened after drug cessation. High-dose intravenous methylprednisolone pulse therapy was applied, and this led to a drastic improvement of his symptoms and signs. CONCLUSIONS: In our case, we suggest that early methylprednisolone intervention can prevent the progression of metronidazole-induced encephalopathy and accelerate neurological recovery. We infer that the progression of encephalopathy is related to the delayed toxicity caused by high dose or concentration of metronidazole.

Rhinovirus-associated acute encephalitis/encephalopathy and cerebellitis.

BACKGROUND: Rhinovirus is a common respiratory pathogen for children throughout the year; nevertheless, its central nervous system involvement is extremely rare, and only two cases have been reported to date: meningitis and sepsis-like illness. PATIENT: A previously healthy 2-year-old Japanese boy developed fever, followed by seizures and lethargy. His cerebrospinal fluid cell count and protein level were slightly increased; brain magnetic resonance imaging showed abnormal intensities in the bilateral cerebellar dentate nuclei, which were prominent in diffusion-weighted images. After his consciousness disturbance improved, cerebellar dysfunction became apparent. He was treated symptomatically, without steroids or any other immunosuppressants. He almost recovered within a few months; however, cerebellar atrophy became evident on brain magnetic resonance imaging. Using acute specimens, human rhinovirus A was detected in his throat swab and cerebrospinal fluid. DISCUSSION: Acute cerebellitis, in which cerebellar inflammation is predominant, is occasionally accompanied by cerebral symptoms, such as consciousness disturbance and seizures. As a causative pathogen, rotavirus is the most common; however, rhinovirus-associated acute encephalitis/encephalopathy and concurrent cerebellitis have not been reported before. Further research, using recent molecular techniques to detect various central nervous system pathogens, including rhinovirus, is needed to delineate the underlying pathophysiology.

A new MRI marker of ataxia with oculomotor apraxia.

PURPOSE: Evaluate the specificity and sensitivity of disappearance of susceptibility weighted imaging (SWI) dentate nuclei (DN) hypointensity in oculomotor apraxia patients (AOA). METHOD: In this prospective study, 27 patients with autosomal genetic ataxia (AOA (n = 11), Friedreich ataxia and ataxia with vitamin E deficit (n = 4), and dominant genetic ataxia (n = 12)) were included along with fifteen healthy controls. MRIs were qualitatively classified for the presence or absence of DN hypointensity on FLAIR and SWI sequences. The MRIs were then quantitatively studied, with measurement of a ratio of DN over brainstem white matter signal intensity through manual delineation. The institutional review board approved this study, and written informed consent was obtained. In the cross-sectional analysis, the Mann-Whitney test was applied. RESULTS: Qualitatively, the eleven AOA patients presented absence of both DN SWI and FLAIR hyposignals; three dominant genetic ataxia patients had moderate SWI DN hyposignal and absent FLAIR hyposignal; the thirteen remaining subjects presented normal SWI and FLAIR DN hyposignal. Absence of DN SWI hypointensity was 100% sensitive and specific to AOA. Quantitative signal intensity ratio (mean ± standard deviation) of the AOA group (98·96 ± 5·37%) was significantly higher than in control subjects group (76.40 ± 8.34%; p < 0.001), dominant genetic ataxia group (81·15 ± 9·94%; p < 0·001), and Friedreich ataxia and ataxia with vitamin E deficit group (87·56 ± 2·78%; p < 0·02). CONCLUSION: This small study shows that loss of the normal hypointensity in the dentate nucleus on both SWI and FLAIR imaging at 3 T is a highly sensitive and specific biomarker for AOA.

Metronidazole induced encephalopathy: case report and discussion on the differential diagnoses, in particular, Wernicke's encephalopathy.

Metronidazole induced encephalopathy is a rare central nervous system toxicity, which may be completely reversible with prompt cessation of metronidazole usage. We present a case of metronidazole induced encephalopathy in a 59-year-old man with a history of Whipple's procedure for pancreatic neuroendocrine tumour. The characteristic magnetic resonance imaging features of metronidazole induced encephalopathy and its main differential diagnosis, Wernicke's encephalopathy, are discussed.

Gadoterate Meglumine Administration in Multiple Sclerosis has no Effect on the Dentate Nucleus and the Globus Pallidus Signal Intensities.

RATIONALE AND OBJECTIVES: Previous studies on possible accumulation of gadolinium-based contrast agents (GBCA) in the brain suggest that macrocyclic GBCA are less likely to accumulate than linear GBCA. However, conflicting results have been reported, especially in MS. The aim of this study is to investigate retrospectively the correlation between gadoterate-meglumine (macrocyclic GBCA) use and T1 signal intensity changes (SI) in the dentate nucleus and the GP on unenhanced T1-weighted images in a large cohort of MS patients. MATERIALS AND METHODS: Unenhanced T1-weighted images of 232 MS patients who previously received multiple intravenous administrations of 0.1 mmol/kg of gadoterate-meglumine were reviewed. The change in T1 SI ratios of dentate nucleus/central pons (DN/CP) and globus pallidus/centrum semiovale (GP/CSO) was calculated between the first and last MRIs and correlated with age, number of injections, time interval between MRIs, disease duration, activity, and therapy. RESULTS: DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p < 0.0001) between the first and last MRIs. Multivariable analyses of both ratios, controlling for age, disease duration, and time interval between MRIs, showed no significant correlation between the number of gadolinium injections and the differences in DN/CP (standardized beta = -0.018, p = 0.811) or GP/CSO SI ratios (standardized beta = -0.049, p = 0.499). CONCLUSION: Repeated administration of gadoterate-meglumine in MS patients did not result in increased T1 SI in the DN or the GP. The significant decrease of GP/CSO ratio between the first and last MRIs is not due to gadolinium accumulation but rather to varying MR parameters.

Main inherited neurodegenerative cerebellar ataxias, how to recognize them using magnetic resonance imaging?

Ataxia is a neurodegenerative disease resulting from brainstem, cerebellar, and/or spinocerebellar tracts impairments. Symptoms onset could vary widely from childhood to late-adulthood. Autosomal cerebellar ataxias are considered as one of the most complex group in neurogenetics. In addition to their genetic heterogeneity, there is an important phenotypic variability in the expression of cerebellar impairment, complicating the genetic mutation research. A pattern recognition approach using brain MRI measures of atrophy, hyperintensities and iron-induced hypointensity of the dentate nuclei, could be therefore helpful in guiding genetic research. This review will discuss a pattern recognition approach that, associated with the age at disease onset, and clinical manifestations, may help neuroradiologists differentiate the most frequent profiles of ataxia.

Effects of serial macrocyclic-based contrast materials gadoterate meglumine and gadobutrol administrations on gadolinium-related dentate nuclei signal increases in unenhanced T1-weighted brain: a retrospective study in 158 multiple sclerosis (MS) patients.

PURPOSE: To perform T1 signal intensity (SI) measurements in the dentate nuclei of adult patients with confirmed multiple sclerosis (MS) after serial administrations of the macrocyclic gadolinium-based contrast agents (GBCAs), gadoterate meglumine and gadobutrol. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and informed consent was waived. A review of our PACS database for the period from March 1, 2007 to July 31, 2016 revealed 158 confirmed MS patients who received exclusively either gadoterate meglumine (n = 81) or gadobutrol (n = 77) for diagnosis and follow-up. SI measurements on unenhanced T1-weighted images were performed on all scans of all patients and at regions of interest (ROIs) positioned on the dentate nucleus (DN) and pons. The dentate nucleus-to-pons (DNP) T1-SI ratio was subsequently calculated. Unpaired T test and regression analysis were used to evaluate statistical differences. RESULTS: An increase in DNP was noted between the first and last MR examinations for both gadoterate meglumine (0.0032 ± 0.0216) and gadobutrol (0.0019 ± 0.0346). Although the differences were not statistically significant based across the entire patient population, visible T1 hyperintensity in the DN was noted in approximately one-third of all patients in each group that received at least five administrations of either GBCA. CONCLUSIONS: SI increases on unenhanced T1-weighted images possibly indicative of gadolinium retention occur after serial administrations of the macrocyclic GBCAs, gadoterate meglumine and gadobutrol.

The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression.

Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We performed clinical evaluation and brain MRI in 38 CTX patients. Sixteen of them who were untreated at baseline examination underwent clinical and MRI follow-up after long-term treatment with CDCA. Brain MRI abnormalities included cortical and cerebellar atrophy, and T2W/FLAIR hyperintensity involving subcortical, periventricular, and cerebellar white matter, the brainstem and the dentate nuclei. Regarding the dentate nuclei, we also observed T1W/FLAIR hypointensity consistent with cerebellar vacuolation and T1W/FLAIR/SW hypointense alterations compatibly with calcification in a subgroup of patients. Long-term follow-up showed that clinical and neuroradiological stability or progression were almost invariably associated. In patients with cerebellar vacuolation at baseline, a worsening over time was observed, while subjects lacking vacuoles were clinically and neuroradiologically stable at follow-up. The brains of CTX patients very often show both supratentorial and infratentorial abnormalities at MRI, the latter being related to clinical disability and including a wide spectrum of dentate nuclei alterations. The presence of cerebellar vacuolation may be regarded as a useful biomarker of disease progression and unsatisfactory response to therapy. On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis.

Cerebellar lobules and dentate nuclei mirror cortical force-related-BOLD responses: Beyond all (linear) expectations.

The relationship between the BOLD response and an applied force was quantified in the cerebellum using a power grip task. To investigate whether the cerebellum responds in an on/off way to motor demands or contributes to motor responses in a parametric fashion, similarly to the cortex, five grip force levels were investigated under visual feedback. Functional MRI data were acquired in 13 healthy volunteers and their responses were analyzed using a cerebellum-optimized pipeline. This allowed us to evaluate, within the cerebellum, voxelwise linear and non-linear associations between cerebellar activations and forces. We showed extensive non-linear activations (with a parametric design), covering the anterior and posterior lobes of the cerebellum with a BOLD-force relationship that is region-dependent. Linear responses were mainly located in the anterior lobe, similarly to the cortex, where linear responses are localized in M1. Complex responses were localized in the posterior lobe, reflecting its key role in attention and executive processing, required during visually guided movement. Given the highly organized responses in the cerebellar cortex, a key question is whether deep cerebellar nuclei show similar parametric effects. We found positive correlations with force in the ipsilateral dentate nucleus and negative correlations on the contralateral side, suggesting a somatotopic organization of the dentate nucleus in line with cerebellar and cortical areas. Our results confirm that there is cerebellar organization involving all grey matter structures that reflect functional segregation in the cortex, where cerebellar lobules and dentate nuclei contribute to complex motor tasks with different BOLD response profiles in relation to the forces. Hum Brain Mapp 38:2566-2579, 2017. © 2017 Wiley Periodicals, Inc.

Ataxia in a chronic kidney disease patient on anti-tubercular therapy.

Isoniazid is the mainstay of anti-tubercular therapy. Used in isolation or in combination with other anti-tubercular drugs, it is generally well-tolerated. While hepatotoxicity and neurotoxicity are reported, significant neurotoxicity remains uncommon. In this report, we present a case of rare neurological complication secondary to anti-tubercular therapy in a patient with stage 5 chronic kidney disease.