Magnetic Resonance Characteristics of Baló Concentric Sclerosis in Children.

BACKGROUND: Baló concentric sclerosis is a rare demyelinating disease with characteristic magnetic resonance appearance of multilayered ringlike lesions of demyelination. This disease is extremely rare in children. We present the clinical data, radiological appearance, and development of lesions in eight children. METHODS: We analyzed the clinical information of eight patients diagnosed between 2012 and 2020. Magnetic resonance brain and spinal cord examinations with contrast medium administration were performed using a 1.5-T scanner. RESULTS: All patients presented at least one typical Baló lesion on brain imaging. Four patients additionally had typical multiple sclerosis plaques. All primary Baló lesions had a characteristic appearance of concentric hyperintense rings on T2-weighted imaging and were round or ovoid. Cerebrospinal fluid analysis was performed in all patients. Oligoclonal bands were present in seven patients, and four of them had multiple sclerosis plaques on baseline brain magnetic resonance imaging. CONCLUSION: Baló concentric sclerosis in children is characterized by acute and severe onset with hemiparesis as a predominant symptom. The size, contrast enhancement, and restricted diffusion depend on the phase of the disease.

From Baló's concentric sclerosis to multiple sclerosis: a series of 6 patients.

INTRODUCTION: Baló's concentric sclerosis (BCS) is a rare CNS disorder characterized by alternating bands of demyelination on MRI. One of the main issues is its relationship with multiple sclerosis (MS). OBJECTIVES: To describe 6 BCS patients. To review the risk of developing MS in BCS patients. METHODS: We retrospectively recorded clinical and radiological findings of 6 BCS patients and performed a review of the literature. RESULTS: Six patients (5 women) with a mean age of 25 years old were included. Main symptoms were hemiparesis/hemihypoesthesia. On MRI, two patients had a single BCS lesion and four had additional MS-like lesions. Alternating bands were usually more visible on DWI. A patient had reduced central perfusion and SWI hypointensity suggestive of a central vein. Oligoclonal bands were identified in 5/6 patients. After 7 years of follow-up, all patients achieved MS criteria with mild disability (mean EDSS 1.75; 0-4). Our literature review included 65 BCS patients from 30 studies: although CSF oligoclonal bands and the presence of additional MS lesions were associated with subsequent relapses, this was not significant. DISCUSSION/CONCLUSION: Our series allows a detailed MRI description in BCS and gives a new insight into BCS evolution and its strong relationship with MS.

Tumefactive inflammatory leukoencephalopathy in cocaine users: Report of three cases.

BACKGROUND: Cocaine is the most common illicit stimulant drug used in Europe, and it can potentially affect the central nervous system due to a direct effect, or by means of additive drugs. Levamisole has been increasingly used as an additive drug since it extends the stimulating effects of cocaine. This has led to an increase in the detection of levamisole adverse reactions, including levamisole-induced multifocal inflammatory leukoencephalopathy (MIL), a potentially lethal monophasic cerebral demyelinating disease. METHODS: We present three adult patients who developed a MIL with tumefactive demyelinating lesions, leading to encephalopathy and motor manifestations. All these patients had in common a history of chronic or acute use of cocaine. Imaging findings revealed a tumefactive MIL, following a Balo's Concentric Sclerosis (BCS) pattern in two cases. RESULTS: The pathophysiology of levamisole-induced MIL may depend on an immunological mechanism, producing multiple demyelinating lesions affecting the subcortical and periventricular white matter, basal ganglia and/or brainstem. Atypical demyelinating lesions are an unusual finding in levamisole-induced MIL. Specifically, the BCS pattern is a rare finding in these patients: to our knowledge, only two more cases mimicking BCS have been reported in the literature, which have also occurred in chronic cocaine users. CONCLUSIONS: Based on the history and images of our patients and other two similar case reports, we suggest a probable pathophysiological relationship between levamisole-adulterated cocaine use and the occurrence of MIL with atypical demyelinating lesions, even when they present following a BCS imaging pattern.

Recurrent schilder's disease.

Schilder's disease is a rare and aggressive central nervous system demyelinating disorder that is typically monophasic and steroid responsive. Here, we present an unusual case of a teenager with Schilder's disease who was treated with corticosteroids and had a clinical and radiographic recurrence nearly one year after the initial presentation.

Specific EEG markers in POLG1 Alpers' syndrome.

OBJECTIVE: To examine whether rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS) in EEG allow a reliable early diagnosis of Alpers-Huttenlocher syndrome (AHS) and contribute to recognition of this disease. METHODS: EEGs of nine patients with DNA-proven AHS and fifty age-matched patients with status epilepticus were retrospectively examined by experts for the presence of RHADS and for accompanying clinical signs and high-frequency ripples. Reproducibility of RHADS identification was tested in a blinded panel. RESULTS: Expert defined RHADS were found in at least one EEG of all AHS patients and none of the control group. RHADS were present at first status epilepticus in six AHS patients (67%). Sometimes they appeared 5-10 weeks later and disappeared over time. RHADS were symptomatic in three AHS patients and five AHS patients showed distinct ripples on the (poly)spikes of RHADS. Independent RHADS identification by the blinded panel resulted in a sensitivity of 87.5% (95% CI 47-100) and a specificity of 87.5% (95% CI 77-94) as compared to the experts' reporting. CONCLUSION: RHADS are a highly specific EEG phenomenon for diagnosis of AHS and can be reliably recognized. Clinical expression and EEG ripples suggest that they signify an epileptic phenomenon. SIGNIFICANCE: RHADS provide a specific tool for AHS diagnosis.

Clinicopathologic Findings of CARS2 Mutation.

OBJECTIVES: We describe a 13-year-old girl with a past medical history of epilepsy, intellectual impairment, dysphagia with gastric tube dependence, and autism spectrum disorder who presented with focal status epilepticus. METHODS: Video-electroencephalography revealed left occipital pseudoperiodic epileptiform discharges and frequent seizures originating from the left hemisphere. The seizure was refractory to antiepileptic medications and pharmacologic coma. Subsequently, left occipital lobectomy was done. Extensive evaluation including whole exome sequencing, histopathologic examination of brain and muscle samples, mitochondrial DNA content analysis of tissue sample was completed to detect the etiology. RESULTS: Skeletal muscle mitochondrial DNA content (qPCR) analysis showed approximately 37% of the mean value of age and tissue matched control group consistent with a mitochondrial depletion syndrome. Microscopic examination of the brain showed cortical abnormalities that largely consisted of infarct-like pathology in a laminar manner, abnormalities of neuronal distribution, and white matter changes. Compound heterozygous mutations of the CARS2 gene were identified by whole exome sequencing; V52G variant [p.Val52Gly (GTG>GGG):c.155 T>G in exon 1] was inherited from the mother and T188M variant[p.Thr188Met (ACG>ATG): c.563 C>T in exon 5] was inherited from the father. CONCLUSION: This is the first detailed clinicopathologic description of the Alpers-Huttenlocher syndrome phenotype from CARS mutations.

Balo's concentric sclerosis: an update and comprehensive literature review.

Balo's concentric sclerosis (BCS) is considered a variant of multiple sclerosis characterized by concentric lamella of alternating demyelinated and partially myelinated tissues. It is a rare and a relatively acute condition. Attacks may proceed rapidly over weeks or months, typically without remission, like Marburg's variant, resulting in death or severe disability. However, the majority of cases have a more benign, self-limiting course with spontaneous remission. Magnetic resonance imaging is a primary imaging modality in the diagnosis of BCS. Treatment with intense immunosuppression may be indicated in patients with more aggressive form. New reports reveal more evidence regarding the pathophysiology and treatment strategies.

Esclerosis concéntrica de Balo: una presentación que simula un ictus isquémico / Balo concentric sclerosis: a presentation mimicking ischaemic stroke

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Myoclonus epilepsy in mitochondrial disorders.

Mitochondrial disorders is a group of clinical entities associated with abnormalities of the mitochondrial respiratory chain (MRC), which carries out the oxidative phosphorylation (OXPHOS) of ADP into ATP. As the MRC is the result of genetic complementation between two separate genomes, nuclear and mitochondrial, OXPHOS failure can derive from mutations in either nuclear-encoded, or mitochondrial-encoded, genes. Epilepsy is a relatively common feature of mitochondrial disease, especially in early-onset encephalopathies of infants and children. However, the two most common entities associated with epilepsy include MERRF, for Myoclonic Epilepsy with Ragged Red Fibers, and AHS, or Alpers-Huttenlocher syndrome, also known as hepatopathic poliodystrophy. Whilst MERRF is a maternally inherited condition caused by mtDNA mutations, particularly the 8344A>G substitution in the gene encoding mt-tRNALys, AHS is typically caused by recessive mutations in POLG, encoding the catalytic subunit of polymerase gamma, the only mtDNA polymerase in humans. AHS is the most severe, early-onset, invariably fatal syndrome within a disease spectrum, which also include other epileptogenic entities, all due to POLG mutations and including Spino-cerebellar Ataxia and Epilepsy (SCAE). This review reports the main clinical, neuroimaging, biochemical, and molecular features of epilepsy-related mitochondrial syndrome, particularly MERRF and AHS.

Morphogenesis of the demyelinating lesions in Baló's concentric sclerosis.

In tissues with elastic properties, an edema causes a raised tissue pressure and therefore a diminished blood flow. The authors assume that an increased tissue pressure due to local and/or relapsing edema may be the cause for incomplete necrosis (e.g. demyelinated lesions) or seldom complete necrosis in the brain. Newly forming demyelinating lesions seldom show small tissue bands with normal appearing myelin sheaths in the immediate vicinity of precursor lesions (Baló type of MS). The small myelinated bands are the result of a "protected zone" on the edge of previous demyelinated lesions. The authors explain this protected zone with two arguments. Firstly, the resorptive granulation tissue of more or less older lesions is relatively rich in capillaries. These capillaries may act as an energy reservoir that can nourish not only the plaque, but also a narrow adjacent myelinated tissue band by diffusion, even if the capillary blood flow in this tissue band is limited due to the greater tissue pressure of a new developing lesion in the neighborhood. Secondly, another protective mechanism may act simultaneously: older or more sclerosed lesions and small adherent bands of myelinated tissue with them may swell less in cases of an edema than in normal tissue. The hardening of the older lesions is caused by proliferated fiber-forming astrocytes in the sense of scarring. In an area with an increased tissue pressure, the capillaries are less compressed in a sclerosed lesion than in regions of normal grey and white matter. In addition, the adherent myelinated tissue band closest to the edge of a hardened plaque is better protected against swelling and compression than the further away tissue. Theoretically, this protection zone is comparable with protected blood vessels in the Haversian canals or the medullary spaces of bones. Both theses of protecting mechanisms at the edges of demyelinated lesions support the assumption of a hypoxic causation principle of demyelinating lesions in Baló's concentric sclerosis and multiple sclerosis.

Baló's concentric sclerosis and tumefactive demyelination: a shared immunopathogenesis?

Baló's concentric sclerosis (BCS) and tumefactive demyelination (TD) are considered atypical forms of multiple sclerosis (MS). Baló lesions are characterized by concentric rings corresponding to alternating bands of demyelination and relatively preserved myelin (Hu and Lucchinetti, 2009). Tumefactive lesions are pseudotumoural demyelinating lesions of >2 cm and may have an open ring-enhancing magnetic resonance imaging appearance (Hu and Lucchinetti, 2009; Lucchinetti et al., 2008; Altintas et al., 2012). We present a patient who developed limb weakness and focal seizures secondary to a lesion radiologically and histopathologically consistent with BCS who, six months later, developed a tumefactive demyelinating lesion. This is the first description of BCS and TD occurring in the same patient and is particularly notable because of the lack of any other more typical demyelinating lesions on the MRIs. The nature of BCS and TD in relation to more typical multiple sclerosis is discussed.

First use of alemtuzumab in Balo's concentric sclerosis: a case report.

Balo's concentric sclerosis (BCS) is a rare demyelinating disorder of the central nervous system. The humanised monoclonal antibody alemtuzumab has shown efficacy in another demyelinating disorder, relapsing-remitting multiple sclerosis. We aimed to explore its efficacy in treatment-refractory BCS. A 52-year-old male with radiologically confirmed progressive BCS resistant to steroids, plasmapharesis and cyclophosphamide was administered a standard protocol of alemtuzumab. Treatment failed to slow his decline; he died 6 months after administration. Why alemtuzumab induced no clinical or radiological impact may be multifactorial. We review the evidence directing BCS therapy and propose the next steps for exploring this potentially fatal condition.

Alpers syndrome: the natural history of a case highlighting neuroimaging, neuropathology, and fat metabolism.

Mitochondrial diseases are increasingly being recognized as causes of encephalopathy and intractable epilepsy. There is no gold-standard test for diagnosing mitochondrial disease, and the current diagnosis relies on establishing a consistent pattern of evidence from clinical data, neuroimaging, tissue biopsy, and biochemical, genetic, and other investigations. Experience in the diagnosis and treatment of patients with certain forms of mitochondrial disease, such as Alpers syndrome, is largely gained from case reports or small case series. The authors describe a case of Alpers syndrome due to POLG1 mutations, including serial neuroimaging and pathological investigations, to illustrate two main points: (1) Unique characteristics evident on serial diffusion-weighted imaging can be a valuable indicator of Alpers syndrome; and (2) abnormal lipid metabolism can be present in Alpers syndrome, which may need to be considered when using a ketogenic diet.

Alpers syndrome with mutations in POLG: clinical and investigative features.

Alpers syndrome is a rare autosomal recessive hepatocerebral degenerative disorder. Seventeen patients with Alpers syndrome or polymerase-γ gene mutations were identified. Case records of 12 patients with Alpers syndrome and polymerase-γ mutations in both alleles were reviewed. All patients manifested developmental delay or regression, refractory epilepsy, and biochemical liver dysfunction. Liver failure occurred in three patients previously treated with valproate. Other signs included ataxia, visual disturbance, motor paresis, and tremor. Myoclonic and focal motor seizures were common, often manifesting as status epilepticus. Electroencephalograms demonstrated absent/slow posterior dominant rhythms. Interictal discharges were common, usually involving the occipital lobes. Rhythmic high-amplitude delta with (poly)spikes was evident in four patients. Magnetic resonance imaging showed migratory, cortical, and subcortical T(2) hyperintensities in four children most often affected the parietal and occipital lobes. Developmental regression and refractory focal motor or myoclonic seizures are consistent clinical features of Alpers syndrome with polymerase-γ mutations. Liver dysfunction constitutes a late manifestation. Migratory T(2)/fluid attenuated inversion recovery signal abnormalities involving metabolically active occipital and sensorimotor cortical regions comprise characteristic imaging findings. Interictal and ictal electroencephalogram patterns are more variable than previously reported. Three common polymerase-γ mutations, in patients of European descent, can assist with rapid diagnosis, circumventing the need for liver biopsy.

Compound heterozygous polymerase gamma gene mutation in a patient with Alpers disease.

Alpers disease is a mitochondrial depletion syndrome characterized by psychomotor retardation, intractable epilepsy, and liver failure. Polymerase gamma (POLG) gene mutations are a known cause of the disease. We describe a case in which a 14-month-old female presented with epilepsia partialis continua evolving into generalized status epilepticus. Treatment with multiple antiepileptic medications and the ketogenic diet eliminated her seizures, but she remained severely encephalopathic. Magnetic resonance imaging showed diffuse atrophy of gray-matter structures. She ultimately developed liver failure and died. Mitochondrial analysis revealed compound heterozygosity for 3 POLG gene mutations, 2 of which were previously unreported.