Balo's concentric sclerosis: An atypical demyelinating disease in pediatrics.

BACKGROUND: Baló's concentric sclerosis (BCS) is a rare subtype of tumefactive demyelinating disease with characteristic radiological and pathological features. In the medical literature, less than 10 BCS cases have been reported in the pediatric population. CASE: We report the case of a 5-year-old boy who presented to the emergency department with 2 days of left-sided weakness. Magnetic resonance imaging (MRI) revealed 3 tumefactive lesions; further diagnostic studies included MRI spectroscopy, lumbar puncture and biopsy. A final diagnosis of Baló concentric sclerosis was made. He received intravenous methylprednisolone at 30 mg/kg for 5 days, plasma exchange treatment and immunoglobulin G course (2 g/kg/day). The patient was discharged in good condition and asymptomatic; after 8 months of follow-up, he has not presented with new symptoms. CONCLUSION: Baló's concentric sclerosis (BCS) is a rare variant of tumefactive demyelinating disease with only a handful of cases reported in the pediatric population. It poses a diagnostic challenge and therapeutic enigma, since it is difficult to distinguish from a central nervous system (CNS) neoplasm, infection or other CNS lesions on magnetic resonance imaging (MRI). Our case along with those reported in the literature, highlights the importance of considering BCS as a potential differential diagnosis when assessing tumefactive lesions. Distinguishing tumefactive demyelinating lesions from malignancy or infection is critical for proper patient management and to avoid unnecessary medical or surgical interventions.

Why Is This Auntminnie a Diagnostic Conundrum?: A Knowledge-Based Approach to Balo's Concentric Sclerosis From Reports of 3 Cases and Pooled Data From 68 Other Patients in the Literature.

INTRODUCTION: We came across 3 cases of Balo's concentric sclerosis (BCS). The first of these patients presented to an outside hospital and was transferred to our institution due to complications resulting from a biopsy. The other 2 patients, despite having a characteristic imaging appearance and despite insistence on our part on the diagnosis of BCS, underwent a surgical procedure, which could have been prevented. This led us to review the available literature on BCS. MATERIAL AND METHODS: A total of 68 patients diagnosed with BCS between 1995 and 2015 were studied and the data collected for the clinical presentation and course, imaging, spinal fluid analysis, treatment, and clinical and imaging outcome. CONCLUSIONS: A 25% surgery rate (biopsy or resection) was found in the study. We concluded that this relatively high surgery rate in this auntminnie nonsurgical disease is multifactorial; and includes factors like nonfamiliarity with the disease, anxiety on the part of patients and physicians, due to a sometimes rapidly deteriorating clinical picture; and resemblance of the disease with other entities such as tumor and infection. However, characteristic imaging appearance combined with acute or subacute presentation and dramatic improvement in clinical status after high-dose steroid chemotherapy; are highly suggestive of the disease, and can prevent unnecessary surgery.

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.

Baló's concentric sclerosis.

Baló's concentric sclerosis is often regarded as a rare variant of multiple sclerosis. Patients with this disorder present with acute or subacute neurological deterioration, with MRI showing one or more concentrically multilayered ring-like lesions usually in the cerebral white matter. Historically, Baló's concentric sclerosis was thought fatal in all cases. However, the availability of MRI has led to a better appreciation of the variable natural history of patients presenting with radiologically evident Baló lesions and the clinical association with multiple sclerosis and, less often, with other neurological disorders. Important advances have increased understanding of the immunopathogenic mechanisms associated with the formation of Baló lesions. However, how to treat an acute lesion and when or whether to start treatment are less well understood, although for patients with Baló lesions who also fulfil standard diagnostic criteria for multiple sclerosis, our opinion is that treatment with multiple sclerosis disease-modifying therapy would seem reasonable.

Balo concentric sclerosis in children: a case series.

Baló concentric sclerosis is a unique and rare phenomenon in demyelinating disease. Typically thought of as a subtype of multiple sclerosis, Baló concentric sclerosis is characterized pathologically by striking rings of demyelination alternating with areas of preserved myelination. Its exact prevalence in adult and especially pediatric populations is unknown. Although traditionally considered to be an acute and fatal disease of adults, there are a handful of reports of Baló concentric sclerosis cases in pediatric patients. Here we report Baló concentric sclerosis-like demyelinating disease in 3 female pediatric patients, representing 2.2% of a cohort of 134 pediatric patients with demyelinating diseases who have been seen in our center since 2005. The relatively high prevalence of Baló concentric sclerosis-like cases in our pediatric demyelinating diseases center, none of which have been fatal, supports the premise that the developing immune and central nervous systems may manifest and respond to demyelinating disease differently from adults.

Mitochondrial hepatopathy in adults: a case series and review of the literature.

AIM: Mitochondrial diseases affect about 1/5000-1/10000 in the population. Twenty percent of patients with mitochondrial disease show liver involvement. In contrast to current belief among most internists, these diseases do not only present in childhood. METHODS: We present four cases of adults (three with Alpers-Huttenlocher syndrome and one with mitochondrial neurogastrointestinal encephalomyopathy), diagnosed between 2005 and 2010, in our university referral center. RESULT: We focus on the broad clinical spectrum of liver involvement in mitochondrial diseases and their diagnosis. Biochemical investigations are often found to be inconclusive, and genetic confirmation cannot always be obtained, leaving many patients without a final diagnosis. Evidence-based causal therapy is unavailable for most mitochondrial diseases and liver transplantation for this indication remains a controversial issue. CONCLUSION: For clinicians, it is important to consider the possibility of an underlying mitochondrial disorder when there is systemic involvement (more than one organ affected), a suggestive family history, or an elevated level of lactic acid in the blood or cerebrospinal fluid.

Schilder's disease: non-invasive diagnosis and successful treatment with human immunoglobulins.

Schilder's disease (SD) is a rare variant of multiple sclerosis with a predilection to children. It is characterized by focal neurological abnormalities, which are atypical for MS, in conjunction with tumor-like white matter lesions on MRI. We report the case of an 11-year-old girl that demonstrates two important features of the disease: a) the clinical presentation and subsequent course in conjunction with the serial neuroradiological findings stress the feasibility of a non-invasive diagnosis of SD; and b) we report a significant clinical response to treatment with intravenous human Immunoglobulins.

The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders.

Disorders of oxidative phosphorylation and mitochondrial function can be caused from mutations involving both mitochondrial DNA (mtDNA) or mitochondrial-targeted nuclear DNA genes. Progressive depletion of mtDNA is one mechanism of mitochondrial dysfunction leading to human disease, which is the end result of loss of the sufficient mtDNA-encoded proteins for normal electron transport chain function. Mitochondrial DNA depletion is caused by germline deletions and duplications of segments within the mtDNA as well as germline mutations in the nuclear genes responsible for mtDNA duplication (the polymerase apparatus including POLG, POLG2 and PEO1) and mtDNA maintenance (those genes that regulate the deoxynucleotide triphosphate pools and other functions including TP1, TK2, DGUOK, SUCLA1, SUCLA2, ANT1, RRM2B and MPV17). This review will focus on the most common disorders that result from mutations with POLG, with some discussion of the other nuclear-encoded genes involved in mtDNA maintenance. Mutations in POLG can cause a wide range of disease, which vary in both age of onset and severity. These disorders comprise a continuous spectrum of overlapping symptoms and signs; and range from a rapidly fatal infantile cerebrohepatic disease to a progressive external ophthalmoplegia (PEO) that may not present until the sixth decade of life. Many of the disorders seem to have a more unique and restrictive clinical presentation, at least to date. Since the first disorders linked to mtDNA depletion were described in 2001, the nomenclature, methods of diagnosis, clinical evaluation and treatment of these disorders have been better defined. However, this remains a rapidly evolving field, with additional proteins and genes are being discovered as DNA testing becomes part of the standard of care in everyday medical practice.

Spinal cord involvement in Balo's concentric sclerosis.

We present a patient with a history of myelitis, who had a steroid refractory attack of CNS inflammatory demyelinating disease that developed into cerebral concentric sclerosis of Balo after plasma exchange. The acute inflammatory disease involved the spinal cord, a phenomenon rarely demonstrated. This patient fulfilled the McDonald criteria for multiple sclerosis. Plasmapheresis did not have a beneficial effect, but the patient stabilised at high EDSS after treatment with mitoxantron.

Juvenile Alpers disease.

BACKGROUND: Alpers disease is commonly associated with polymerase gamma deficiency and usually affects infants or young children. OBJECTIVE: To report a juvenile case of Alpers disease due to mutations in the polymerase gamma gene (POLG1). DESIGN: Clinical, pathologic, biochemical, and molecular analysis. SETTING: Tertiary care university hospital and academic institutions. PATIENT: A 17-year-old adolescent girl with intractable epilepsy and liver disease. MAIN OUTCOME MEASURES: Clinical course and pathologic, biochemical, and molecular features. RESULTS: Biochemical and pathologic evidence suggested a respiratory chain defect, which was confirmed by enzyme analysis of the liver. Mutational analysis of POLG1 showed 2 novel mutations: T851A and R1047W. CONCLUSION: The POLG1 mutations can cause juvenile and childhood Alpers disease.

Alpers syndrome: progressive neuronal degeneration of children with liver disease.

Alpers syndrome was not clearly defined until the link between brain and liver disease was described. Alpers syndrome can now be clearly established as a disorder of oxidative metabolism related to mitochondrial dysfunction, and in most instances with an autosomal mode of inheritance. The symptoms and signs are discussed. The illness occurs in the first years of life with the sudden onset of intractable seizures associated with developmental delay, hypotonia, ataxia, cortical blindness, and hepatic failure, and death occurs within a short time. Treating the seizures with valproic acid can cause the rapid onset of liver failure and must be avoided. To establish a definite diagnosis, liver and muscle biopsies may be needed. The former shows bile duct proliferation with the evidence of cirrhosis, and the latter may support the involvement of the mitochondrial respiratory chain if there are ragged-red fibres. Genetic studies can show an association with mitochondrial DNA depletion and mutations in the polymerase gene. Cytochrome c oxidase deficiency has been demonstrated in some patients. Useful diagnostic tests include liver function tests, lactic acid levels in the blood and cerebrospinal fluid, electroencephalograms, computed tomography, and magnetic resonance imaging. The differential diagnosis will be from other forms of neuronal degeneration and disorders of mitochondrial function. There is no specific treatment, which must await further research into causes.

Embryonic stem cell-derived glial precursors: a source of myelinating transplants.

Self-renewing, totipotent embryonic stem (ES) cells may provide a virtually unlimited donor source for transplantation. A protocol that permits the in vitro generation of precursors for oligodendrocytes and astrocytes from ES cells was devised. Transplantation in a rat model of a human myelin disease shows that these ES cell-derived precursors interact with host neurons and efficiently myelinate axons in brain and spinal cord. Thus, ES cells can serve as a valuable source of cell type-specific somatic precursors for neural transplantation.

Presentation, management and follow-up of Schilder's disease.

Schilder's diffuse myelinoclastic sclerosis is a rare demyelinating disease which often mimics intracranial neoplasm or abscess. We have treated 3 patients with this disorder in the past 5 years and followed their postoperative course. Certain distinct features of this disease will allow neurosurgeons to preoperatively entertain this diagnosis. We discuss postoperative treatment and propose a new hypothesis regarding the variable prognoses of this disorder. Schilder's disease constitutes an important diagnosis for any neurosurgeon to be aware of (especially those treating the pediatric age group) which has not received adequate coverage in the neurosurgical literature.

Serial magnetic resonance imaging (MRI) study of a patient with Balo's concentric sclerosis treated with immunoadsorption plasmapheresis.

A 28-year-old Japanese woman with Balo's concentric sclerosis developed a rapidly progressive form of encephalopathy. Magnetic resonance imaging (MRI) showed multiple concentric lesions in the central white matter and the cerebellum. The administration of corticosteroid regimen resulted in little benefit. Immunoadsorption plasmapheresis led to a remission within 1 month of onset. Serial MRI study was described here for the first time, which allowed us to observe the development of concentric structures. The observation indicated that, initially, a central core, a round demyelinated area, and surrounding edema appeared around a vessel. Subsequently, concentric demyelinated bands formed simultaneously, not centrifugally, with diminution of the edema. Analysis of cerebrospinal fluid showed elevated levels of interleukin-6 and tumor necrosis factor-alpha. The success of immunoadsorption plasmapheresis therapy in this patient suggests that both humoral demyelinating factors and cell-mediated immunity may be involved in the pathogenesis of this disorder.

Selected leukodystrophies.

The clinicopathologic profiles of the major leukodystrophies (adreno-leukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy or Krabbe's disease, Pelizaeus-Merzbacher disease, and spongy degeneration of infancy or Canavan's disease) are reviewed. Particular attention is paid to distinctive imaging characteristics, molecular advances, pathogeneses, and potential therapies.