Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study

Vacuolating megalencephalic leukoencephalopathy (VML) with subcortical cysts is a neurodegenerative disorder clinically characterized by megalencephaly with onset in the first year of life, progressive ataxia, spasticity and relatively spared cognitive function. Conventional MRI findings consist of diffusely abnormal cerebral white matter with subcortical cysts. Recent single-voxel proton MR spectroscopy studies have shown mild metabolic abnormalities in the white matter. We report here a combined proton MR imaging and MR spectroscopic imaging (1H-MRSI) study on 2 new, unrelated patients with this rare disorder. 1H-MRSI examinations, which can provide simultaneously metabolic information from many different brain regions, showed inhomogeneous decreases in all normally detected metabolites with significant widespread decreases in the ratio of N-acetylaspartate to creatine+phosphocreatine and concomitant small increases in lactate in the white matter of both hemispheres. Metabolic abnormalities were milder in the frontal white matter and more severe in the posterior white matter. The 1H-MRSI pattern of the gray matter was normal in both patients. In one patient, a subsequent 1H-MRSI examination (performed 3 years after the first) confirmed the presence of widespread decreases in the ratio of N-acetylaspartate to creatine+phosphocreatine in the white matter. We conclude that severe metabolic abnormalities can be found in the white matter of VML patients. This suggests that, despite the apparently mild clinical course, a severe neurodegenerative process may occur in the white matter of these patients.     

Clinical and Magnetic Resonance Imaging Regression of Progressive Multifocal Leukoencephalopathy in an AIDS Patient After Intensive Antiretroviral Therapy

A 36-year-old homosexual man with 6 months of visual symptoms and headaches had right homonymous hemianopia, mild new learning impairment, and alexia with agraphia. The initial brain magnetic resonance imaging (MRI) scan was reported consistent with left occipital infarction. Subsequent MRI demonstrated abnormal demyelination in subcortical white matter and deep parieto-occipital white matter bilaterally, but primarily left. Human immunodeficiency virus testing and cerebrospinal fluid polymerase chain reaction for JC virus DNA were both positive, consistent with progressive multifocal leukoencephalopathy (PML) with AIDS. His clinical status steadily deteriorated, and MRI white matter abnormalities worsened despite high-dose antiretroviral therapy. After the antiretroviral regimen was intensified by the addition of a protease inhibitor, rapid clinical and radiographic improvement occurred with subsequent MRI studies revealing only residual left parieto-occipital encephalomalacia. PML in AIDS patients has been associated with a nearly uniformly poor prognosis until recent reports of improved outcomes after highly active antiretroviral therapy. This patient with PML and AIDS similarly showed a robust clinical and MRI response to intensive antiretroviral combination therapy, which has been maintained for more than 3 years.     

Atypical MRI findings in Kearns-Sayre syndrome: T2 radial stripes

Kearns-Sayre syndrome (KSS) is a mitochondrial disorder consisting of external ophthalmoplegia, retinitis pigmentosa, ataxia and heart block. Magnetic resonance imaging (MRI) shows abnormal T2 high signal intensity in the deep gray matter nuclei, the cerebellar and the subcortical white matter. We report an unusual MR pattern of KSS, where the T2 images revealed radially oriented, hypointense stripes in hyperintense white matter, a characteristic MRI pattern of lysosomal disease not previously reported in KSS.     

Cerebral amyloid angiopathy-related inflammation – A case report presenting diagnostic difficulties

We describe an 86-year-old woman with a history of hypertension who presented sudden disturbances of consciousness and left hemiparesis. Brain magnetic resonance imaging (MRI) revealed diffused hyperintensive changes on T2-weighted images localized subcortically in the white matter of both cerebral hemispheres, corresponding to acute vasogenic edema, causing moderate mass effect. Posterior reversible encephalopathy syndrome was initially diagnosed. After implementation of anti-edema intravenous steroid treatment and hypotensive therapy the symptoms began to retire, till the total regression. The successive hospitalizations took place two and eight months later due to the occurrence of seizures, motor deficits and the development of mild cognitive impairment. Brain MRI revealed progression of the white matter changes and diffused subcortical microhemorrhages. Each time pulse steroid therapy was implemented and the symptoms improved significantly after several days. Chronic oral steroid treatment resulted in the stabilization of neurological status. The long-term observation of clinical symptoms, remission after immunosuppressive therapy and white matter changes with subcortical microhemorrhages in brain MRI leaded to the diagnosis of cerebral amyloid angiopathy-related inflammation.     

Neurophysiology and MRI in late-infantile metachromatic leukodystrophy

We present serial clinical, radiologic, and neurophysiologic findings of a patient with late-infantile metachromatic leukodystrophy who was first admitted at 30 months of age because of gait disturbance. The neurologic findings were consistent with mild spastic diplegia (occasionally with toe walking). Magnetic resonance imaging disclosed diffuse high intensity in the cerebral white matter on T₂-weighted images. Nerve conduction velocity studies and evoked-potential studies were markedly abnormal. Assay of arylsulfatase A activity in leukocyte culture disclosed a marked deficiency of the enzyme, confirming the diagnosis of late-infantile metachromatic leukodystrophy. Serial neurophysiologic studies demonstrated a marked decrease of nerve conduction velocities, both motor and sensory, as well as prolongation or disappearance of brainstem auditory-, visual-, and somatosensory–evoked potential latencies. Magnetic resonance imaging studies revealed initially diffuse increased signal intensity of periventricular and subcortical white matter on T₂-weighted images, progressing to cortical atrophy with involvement of the arcuate fibers and the cerebellar white matter, correlating with the clinical deterioration (severe spastic tetraplegia with optic atrophy and epilepsy).     

Megalencephalic leukoencephalopathy: a further case of a new neurodegenerative white matter disease

The case is presented of a 4.5-year-old boy with cystic megalencephalic leukoencephalopathy who met the diagnostic criteria of a recently described neurodegenerative white matter disorder, i.e. leukoencephalopathy with swelling and a discrepancy mild clinical course (van der Knaap 1995). He demonstrated an extremely mild and slowly progressive clinical course with near normal psychomotor development, particularly of mental functions, which contrasted with somewhat disturbed gross and fine motor skills. Repeated CT and MRI scanning showed extensive hemispheral cerebral white matter changes and demonstrated predominant frontal involvement of the periventricular and subcortical white matter. MRI was more sensitive in the detection of preserved structures, i.e. occipital subcortical and central white matter, as well as in the visualization of swelling and cystic lesions in the tip of the temporal lobes, which represent the hallmark of this entity. Thus, MRI is an essential diagnostic tool for this entity.     

Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a genetic disorder featuring diffuse MRI white matter abnormalities and a discrepantly mild clinical picture. It is related to different mutations in MLC1 gene encoding a putative membrane protein of still unknown function. We report on a genetically proven MLC patient who presented with a peculiar clinical course characterized by a prolonged comatose state following a minor head trauma at 12 years of age. The disturbance of consciousness lasted for over four months and then gradually improved. Proton MR spectroscopic imaging studies showed a moderately severe depletion of N-acetylaspartate restricted to the white matter with sparing of the cortical grey matter. The full recovery from coma suggests a transitory functional impairment of the structures implicated in the maintenance of consciousness.     

Schilder's disease: case study with serial neuroimaging

Schilder's myelinoclastic diffuse sclerosis is a rare sporadic demyelinating disease that usually affects children between 5 and 14 years old. The disease often mimics intracranial neoplasm or abscess. We report a 9-year-old girl with Schilder's disease who presented with left hemiparesis. Cranial computed tomography and magnetic resonance imaging (MRI) showed large lesions in the subcortical white matter of the occipital and parietal lobes of both hemispheres that were indistinguishable from an abscess. A cerebrospinal fluid oligoclonal band test was found positive. A diagnosis of acute disseminated encephalomyelitis was then suspected. Serial MRI examinations revealed regression of parenchymal lesions, but there were new developing corpus callosum lesions. After 2 months, the patient presented with right-sided visual loss. MRI examination revealed a right optic nerve lesion. The patient had a dramatic clinical response to corticosteroid therapy. Subsequent control MRI examination revealed regression of both lesions. At 24 months of observation, the patient continued to do well without any complaints or neurologic sequelae.     

Twelve-year monitoring of a patient with megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is an infantile-onset inherited disease of the brain white matter with a defect in brain ion and water homoeostasis, which leads to an abnormal brain volume regulation. Clinical features of the disease can be variable, but patients typically show early-onset macrocephaly, motor abnormalities, seizures, and almost constant late-onset mild mental deterioration. Brain magnetic resonance imaging (MRI) reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and frontoparietal regions. We describe here clinical findings and volumetric MRI and ¹H-MR spectroscopic imaging (¹H-MRSI) data of a 12-year follow-up on a patient with MLC. The patient had only slight clinical worsening during the long follow-up. Volumetric findings showed substantially unchanged cystic volumes and mild brain atrophy rate. In addition, there was no over time increase in the volume of white matter hypointense lesions seen on FLAIR images at baseline, but the degree of hypointensity of these white matter voxels increased over 12 years. Longitudinal ¹H-MRSI examination showed long-term undetectable metabolite signals in the white matter, whereas the metabolic pattern of gray matter voxels remained unchanged over time. Results show that, in MLC, the chronic brain white matter changes resulting from the brain ion, and water homeostasis can be monitored by quantitative MRI modalities. This might be important for assessing treatment effects.     

Cerebral white matter involvement in children with mitochondrial encephalopathies

In childhood mitochondrial encephalopathies the common MRI features are bilateral symmetric abnormalities in basal nuclei and brainstem. The presence of diffuse white matter abnormality has been described only in a few cases. Among a series of 110 children with mitochondrial encephalopathies, 8 patients with MR imaging consistent with a leukoencephalopathy were retrospectively evaluated. Diagnosis was based on the recognition of the biochemical defect in muscle homogenate. H-MR spectroscopic imaging was performed in six of them. Biochemical analysis demonstrated a defect of respiratory chain complexes in six patients: complex I in two cases, complex II in two, complex IV in one, multiple complexes defect in one. Pyruvate dehydrogenase deficiency was demonstrated in two patients. MRI showed severe involvement of the brain white matter without significant basal nuclei or brainstem abnormalities. Two patients developed large cystic areas since onset; in two others progressive vacuolisation of affected white matter was seen later in the course of the disease. One patient with pyruvate dehydrogenase deficiency also presented with a diffuse cortical polymicrogyria. H-MR spectroscopic imaging showed a decrease of N-acetylaspartate, choline and creatine with lactate accumulation in five patients, and was normal in one. These findings suggest that mitochondrial disorders should be included in the differential diagnosis of white matter disorders.     

Zerebrale lymphomatoide Granulomatose

We present the case of a 57-year-old patient who was admitted with fever and disorientation. The cerebrospinal fluid showed a mild pleocytosis and increased protein content. MR imaging revealed multiple lesions, particularly in the subcortical white matter, with spot like central contrast enhancement. The diagnosis of lymphomatoid granulomatosis was finally made through open lung biopsy. Despite treatment with rituximab and, in the later course of the disease, additionally with cyclophosphamide, the patient died 3 months after the diagnosis was made.     

CT, MRI, and autopsy findings in brain of a patient with MELAS

Brain autopsy findings in a 14-year-old patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes were compared with those of computed tomography (CT) and magnetic resonance imaging (MRI). Pathologic examinations revealed extensive laminar necrosis bordered by gliotic tissues throughout the cerebral cortices. Moderate losses of myelin and fibrous gliosis were also observed in the subcortical and deep white matter. These lesions were demonstrated as low-density areas on CT and as high-signal areas on T2-weighted MRI. MRI revealed the lesions more distinctively and precisely than CT. Neither CT nor MRI could reveal abnormalities in the basal ganglia, including vascular proliferation and calcium deposits in the blood vessels.     

New pattern of brain MRI lesions in isolated complex I deficiency

We describe a boy presenting at the end of the first year of life with severely delayed motor development and only mild mental retardation. Neurological examination revealed axial hypotonia, mild ataxia and pyramidal signs. Elevated lactate and protein in cerebrospinal fluid were the most prominent laboratory abnormalities. Brain MRI showed severe supratentorial white matter changes. Cerebellar white matter appeared normal whereas the signal of the atrophic cerebellar cortex was markedly increased. In vivo 1H-magnetic resonance spectroscopy of the parietooccipital white matter region showed a distinct resonance of lactate. By means of biochemical analysis of respiratory chain enzymes in fibroblasts, the diagnosis of an isolated complex I deficiency could be established in our patient.     

Sequential neuroradiological and neurophysiological studies in a Japanese girl with merosin-deficient congenital muscular dystrophy

We describe the early manifestation and sequential assessment of the central and peripheral nervous system in a Japanese girl with merosin-deficient congenital muscular dystrophy. She showed severe hypotonia (‘‘floppy infant”) and suffered mild respiratory failure postnatally. Serum creatine kinase was elevated to 11,487 IU/L. The muscle biopsy showed dystrophic changes with negative expression of merosin (laminin α2), thereby confirming merosin-deficient congenital muscular dystrophy. Her motor milestones were severely delayed, but she could sit without support at the age of 3 years. After 3 years, her motor ability deteriorated and by the age of 5 years, she could not sit and control her neck. Magnetic resonance imaging (MRI) at 2 months of age revealed patterns that were appropriate for her age. At 1 year of age, the T2 weighted images showed diffuse high signal intensities throughout the centrum semiovale, and periventricular and subcortical white matter of the frontal and occipital lobes, while the U fibers, the corpus callosum and the internal capsule were spared. At the age of 7 years, these white matter abnormalities decreased. MR spectroscopy (MRS) revealed normal values of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr metabolite ratios as well as slightly increased myoinositol (mI)/Cr metabolite ratios. Neurophysiological motor nerve conduction velocity (MCV) and compound muscle action potential (CMAP) of the median nerve were in the normal range at the age of 2 months. After the child reached 1 year of age, the MCV and CMAP lagged behind those of healthy controlled children. The sensory nerve conduction velocity of the median nerve demonstrated a mild delay at the age of 15 months. It improved to normal range at the age of 6 years but decreased at 7 years of age. These sequential findings suggest not only that muscular degeneration and dysmyelination had occurred but also that various other factors, including demyelination and the vasogenic system, may influence the pathology of MDC1A.     

Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children

An identical syndrome of cerebral leukoencephalopathy and megalencephaly with infantile onset was discovered in 8 children, including 2 siblings. Neurological findings were initially normal or near normal, despite megalencephaly and magnetic resonance imaging (MRI) evidence of severe white matter affection. Slowly progressive ataxia and spasticity developed, while intellectual functioning was preserved for years after onset of the disorder. MRI characteristics included diffuse abnormality in signal intensity and swelling of the cerebral hemispheral white matter with cyst-like spaces in the frontoparietal and anterior-temporal subcortical areas. MR spectra were relatively mildly abnormal. Screening for inborn errors, especially those that cause either megalencephaly or white matter disease or both was negative. A distinguishing feature of the present disorder is the apparently severe abnormality of the cerebral white matter as demonstrated by MRI, which contrasts with the remarkably slow course of functional deterioration.     

Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency

We examined brain magnetic resonance imaging (MRI) in a cohort of seven patients with ornithine transcarbamylase deficiency (OTCD), and correlated MRI findings with clinical manifestations. Seven patients with OTCD, aged 3-27 years, all with a missense mutation, were involved in the study. We classified the OTCD patients clinically into four stages. MR study was performed with a 1.5-T superconducting magnet during asymptomatic periods. MRI revealed white matter lesions in two patients with an advanced clinical stage, i.e. T1 and T2 prolongated round lesions in the deep white matter and posterolateral angle of the lateral ventricle in one patient; small foci of T2 and T1 prolongation in the subcortical white matter in another. Parenchymal lesions, and cerebral and cerebellar atrophy were not found in the other five patients. MRI might be normal in the early stage of the disease, and progress in proportion to the clinical stage of OTCD. OTCD should be considered as a differential diagnosis of small foci in the white matter in children.     

Acute posterior multifocal placoid pigment epitheliopathy with cerebral involvement.

In a patient with angiographically proven cerebral vasculitis five months after acute posterior multifocal placoid pigment epitheliopathy (APMPPE) neurological symptoms promptly responded to steroid treatment. Cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis. Magnetic resonance imaging (MRI) revealed multifocal white matter lesions in the hemispheres and the brain stem suggesting a diffuse subcortical vasculitis.     

L-2-Hydroxyglutaric aciduria presenting as status epilepticus

L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare organic aciduria with a slowly progressive course regarding CNS involvement. We present a 13.5-year-old female patient who presented at the Emergency Department with a generalized status epilepticus, which promptly responded to intravenous phenytoin. CT and MRI demonstrated subcortical white matter alterations. The neurological examination revealed mild mental retardation, macrocephaly and ataxic gait with cerebellar signs. Repeated urinary organic acid analysis demonstrated increased excretion of 2-hydroxyglutaric acid which was of the L-configuration. The constellation of macrocephaly in a patient with mental retardation, cerebellar tract involvement and subcortical white matter signal alterations on MRI should alert the physician to the possibility of L-2-HGA. Although rare, epileptic seizures or even status epilepticus can be among the presenting symptoms in organic acidurias with a slow course, such as L-2-HGA.     

Atypical Metronidazole-Induced Encephalopathy in Anaerobic Brain Abscess

Metronidazole-induced encephalopathy is a very rare complication of the long standing use of metronidazole. The encephalopathy is bilateral and symmetric in nature. We report on the magnetic resonance imaging (MRI) and clinical course of metronidazole-induced encephalopathy in a 60-year-old female with a persistent anaerobic brain abscess after draining of the abscess. After 3 months of metronidazole administration, the patient complained of dysarthria, tingling sense of all extremities, and left hemiparesis. MRI revealed symmetric hyperintensity lesions in medulla, pons, dentate nuclei of cerebellum, and splenium of corpus callosum, all of which represent typical findings of metronidazole-induced encephalopathy. In addition, asymmetric lesions in midbrain, thalamus, putamen and cerebral subcortical white matter were noted. The patient recovered after discontinuation of metronidazole and the remaining abscess was successfully treated with meropenem and levofloxacine.     

Conventional MRI and MR spectroscopy in nonclassical mitochondrial disease: report of three patients with mitochondrial DNA deletion

Objects The objectives were to present magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings in three patients with deletion on mitochondrial DNA (mtDNA) and nonclassical mitochondrial disorders (NCMD), correlating these findings with the percentage of deleted mtDNA.Results Our study confirms the high prevalence of white matter (WM), basal ganglia, and posterior fossa lesions in NCMD, ranging from mild to severe involvement. The subcortical WM, caudate, thalamus, globus pallidus, and dorsal brain stem were more frequently affected. A lactate peak was the most frequent finding at the MRS. We found a correlation between the percentage of mtDNA deletion and degree of MRS abnormalities.Conclusions Our findings showed that MRS is a useful investigational tool in patients with NCMD. Supplementary studies are necessary to elucidate the correlation of quantitative mtDNA deletion and neuroimaging phenotype.