Diffuse White Matter Changes Research Articles

A Case of Cocaine-induced Toxic Leukoencephalopathy With Severe Radiologic but Mild Clinical Disease

Objective: To present a case of toxic leukoencephalopathy secondary to cocaine use presenting as mild clinical disease with mainly neurobehavioral symptoms, but relatively severe radiologic disease. Background: The term leukoencephalopathy was first used to describe cerebral white matter changes seen in children with leukemia, but is now used to refer to any of a group of diseases affecting the white substance of the brain. Toxic leukoencephalopathy may be caused by exposure to a wide variety of agents, including cranial irradiation, therapeutic agents, drugs of abuse and environmental toxins. Cocaine-induced toxic leukoencephalopathy is a relatively rare phenomenon with unknown prevalence. Case Presentation: We describe a case of cocaine-induced toxic leukoencephalopathy in a 55-year-old man presenting with confusion, inattention, abulia, and apathy. Infectious work-up and cerebrospinal fluid studies were unremarkable except for a mild elevation of cerebrospinal fluid protein. Magnetic resonance imaging of the brain showing extensive bilateral symmetric leukoencephalopathy is provided, along with a brief discussion of this entity of white matter disease. Conclusions: Cocaine use can manifest as diffuse symmetric white matter changes on magnetic resonance imaging of the brain as well as changes in the basal ganglia and globus pallidus. In the absence of other laboratory and historical abnormalities and in the setting of neurobehavioral disabilities and previous drugs use, it is important to consider cocaine-induced leukoencephalopathy as a differential.

SPG2 mimicking multiple sclerosis in a family identified using next generation sequencing

Several single gene disorders can potentially be overlooked in the differential diagnostic evaluation of patients with multiple sclerosis (MS). Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are allelic X-linked disorders associated with defective myelination of the central nervous system and mutations in PLP1. Neurological symptoms are occasionally observed in female carriers of these mutations.Two women – the proposita (Pt1) and her mother (Pt2) – reported walking difficulties since adolescence and showed progressive cognitive decline. Their neurological examinations revealed spastic gait, pyramidal tract involvement and distal muscle atrophy in the legs. Peripheral neuropathy and diffuse white matter (WM) changes on brain MRI were also observed. Both patients had a preliminary diagnosis of primary progressive MS. Using a targeted method in next generation sequencing, the novel heterozygous c.210T>G/p.Y70* in PLP1 was identified in Pt2. The same mutation was also found in Pt1 but not in five healthy relatives. The mutation showed moderate-to-severe skewed X inactivation in tissues, and Western blotting revealed a significant reduction of PLP1 and DM20 in the sural nerve of Pt2. In conclusion a mother and daughter presented an X-linked dominant disorder with skewed X inactivation. The authors suggest that PLP1 testing might be considered in the evaluation of women with spastic paraparesis, cognitive decline and WM changes.

Differential diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) is an inherited CNS disease, which is caused by mutations in the NOTCH3 gene. Selective disorders of small vessels underlie the disease pathogenesis. Clinically CADASIL is characterized by headaches, multiple stroke-like disorders (in most cases transient ischemic attacks and lacunar strokes), and different focal neurological symptoms and dementia. There are specific MRI signs of the disease: multiple lacunar infarctions located in the basal ganglia, brain steam and cerebellum, focal lesions of temporal poles, capsula externa, periventricular and subcortical areas; diffuse white matter changes and leukoaraiosis can be observed as well. The differential diagnosis of CADASIL is made with many diseases, which are manifested by multiple brain matter lesions, including demyelinating disorders. It should be taken into account that CADASIL is characterized by headaches as one of the initial symptoms, multiple lacunar and diffuse brain matter lesions based on MRI data with an absence of atherosclerosis and arterial hypertension. Family history and autosomal dominant mode of inheritance is also typical of CADASIL. Detection of the NOTCH3 gene mutation is necessary for the definite diagnosis of CADASIL.

Spectrum of MRI brain findings in subacute sclerosing panencephalitis

Background and objectives: Subacute sclerosing panencephalitis (SSPE) is a progressive catastrophic neurodegenerative disease because of persistent measles viral infection in the brain. This study was designed to determine the spectrum of magnetic resonance imaging (MRI) findings in subacute sclerosing panencephalitis. Design: Case series. Methods: We described the brain MRI findings in 20 pediatric patients with confirmed SSPE with their clinical and electroencephalogram (EEG) correlates. This study was conducted at Aga Khan University Hospital, Karachi, Pakistan between January 2006 and June 2016. Diagnosis of SSPE was on the basis of the clinical signs and symptoms, the characteristic EEG patterns (burst suppression in the early stage and a diffuse, random, slow arrhythmia pattern in the late stage), and high titers of measles antibody in the cerebro-spinal fluid. Results: The mean age at presentation was 7.4 ± 3.3 years. MRI abnormalities included diffuse white matter changes (n = 8), subcortical T2 hyperintesities in both grey and white matter in 1 patient and the brainstem changes in 2 patients. MRI was normal in 8/20 patients. Magnetic resonance spectroscopy (MRS) was performed in 4 patients out of whom 1 patient showed reduced N-acetyl aspartate (NAA) peak with elevated choline peak and inverted doublet lactate peak, 1 showed only reduced NAA, 1 showed isolated choline peak and 1 patient had a normal MRS. Conclusion: MRI brain to date is supportive in understanding the pathology of SSPE. MRI can be normal in patients with SSPE if done early on at the start of the disease.

An updated histological classification system for multiple sclerosis lesions.

Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. Inactive lesions are almost completely lacking macrophages/microglia. Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. For this classification of MS lesions, identification of myelin with histological stains [such as luxol fast blue-PAS] or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination.

Long-term effects of white matter changes on the risk of stroke recurrence after carotid artery stenting in patients with symptomatic carotid artery stenosis

IntroductionCerebral white matter changes (WMC) are associated with increased 30-day perioperative risk of stroke in patients undergoing carotid artery stenting (CAS). However, there is no data showing their impact on postoperative long-term stroke recurrence or survival. It remains unknown whether this effect is independent of classic cardiovascular risk factors or not. We tried to assess the effects of WMC on long-term stroke recurrence after CAS in patients with symptomatic carotid stenosis. MethodsA database of patients with symptomatic carotid stenosis who had undergone CAS was sampled in a single Chinese medical center from 2007 to 2014. Copies of baseline brain imaging were analyzed by two investigators to evaluate the severity of WMC. We analyzed the association between WMC and stroke recurrence after CAS by reviewing case histories and conducting telephone interviews, with a mean follow-up time of 28months. Results107 patients with an average age of 66years fulfilled the inclusion criteria, of which 70 were examined with CT and the remainder by MRI. In our cohort, 91.6% of the participants were male. There were 29 patients with diffuse WMC. In univariate analysis, patients with diffuse WMC had more contralateral occlusion than those with non-diffuse WMC. In patients with diffuse WMC, more stroke recurrences were observed compared with those with non-diffuse WMC (hazard ratio [HR] 3.516; 95% CI 1.176, 10.510, P=0.024). ConclusionsIn patients with symptomatic carotid artery stenosis, diffuse WMC were a risk factor for stroke recurrences after CAS. Larger studies are warranted to confirm this finding and explore the potential clinical impact of WMC so as to better determine treatment strategies for patients with symptomatic carotid artery stenosis.

Malignant cerebral edema related to Systemic Lupus Erythematosus

BackgroundThe neurological manifestations of Systemic Lupus Erythematosus (SLE) are varied and incompletely described. A few case series report a benign idiopathic intracranial hypertension (IIH) related to SLE, which is responsive to immunotherapy. There are limited reports of patients with malignant cerebral edema, and diffuse white matter changes in the absence of central nervous system (CNS) vasculitis. MethodsCase series from our tertiary care center and review of the relevant literature. ResultsCase one was a 32year-old woman admitted with nausea, vomiting and cranial nerve palsies. Serology was significant for a diagnosis of probable SLE. MRI was performed and showed bilateral symmetric diffuse T2/FLAIR hyperintensities throughout the white matter and cerebral angiography was unremarkable. The patient developed recalcitrant cerebral edema with intracranial hypertension despite immunosuppressive therapies and subsequently expired. Post mortem evaluation showed a white matter inflammatory process, but no vascular changes consistent with CNS vasculitis. Case two was a 29year-old woman with known SLE that presented with a loss of consciousness. Imaging included a CT that showed diffuse cerebral edema with white matter involvement and a normal cerebral angiogram. Again, despite maximal medical management the patient herniated resulting in death by neurologic criteria. ConclusionsThese two cases represent a syndrome of white matter changes and diffuse cerebral edema associated with SLE that have yet to be reported in the literature. It is unclear if this process has a similar pathology to SLE related IIH. Because this syndrome causes a fulminant cerebral edema, further research is needed to better understand the underlying pathology and identify potential treatment options.

Concepts and opportunities for repair in cerebral microvascular disease and white matter stroke.

Diffuse changes in white matter resulting from cerebral microvascular disease contribute to cognitive impairment (Jokinen et al., 2011), declines in global functionality (Inzitari et al., 2009), and even death (Debette and Markus, 2010). Twenty years ago, estimations of the clinical incidence of cerebral microvascular disease approached 11 million per year in the US alone (Leary and Saver, 2003). More recent estimations suggest the prevalence of diffuse white matter disease and silent brain infarction approaches 20% and increases dramatically in the presence of cardiovascular risk factors (Fanning et al., 2014). Two common clinical presentations of cerebral microvascular disease include diffuse lesions resulting in T2/FLAIR signal abnormality on MRI scans throughout the white matter. Highly related to this diffuse form, is the classic lacunar infarction, with imaging evidence suggesting that new infarcts occur at the leading edge of prior T2/FLAIR signal abnormality (Duering et al., 2013), with subtle changes in axonal diffusivity occurring in the same region (Maillard et al., 2011). Cellular events within this white matter penumbral region are therefore a likely contributor to the progressive nature of white matter disease. Despite the growing prevalence of cerebral microvascular disease, there are no known efficacious treatment strategies to prevent the progression or repair the injury burden of ischemic white matter lesions. In part, this results from a comparative lack of understanding about the precise pathophysiology of cerebral microvascular disease nor the resultant cellular biology that underlies diffuse or focal changes in white matter. This lack of understanding exists because of limitations on the ability to appropriately model white matter lesions in an easily accessible animal model such as the mouse. With the recent development of several variations in a mouse model of focal white matter stroke (Nunez et al., 2016), the field is poised for significant advances in understanding the cellular mechanisms underlying white matter lesions resulting from cerebral microvascular disease and to identify leading strategies to repair ischemic white matter lesions. Here, we outline the neurobiologic concepts and major strategies for repair of diffuse cerebral microvascular disease and white matter stroke (Figure 1).

White matter abnormalities are associated with chronic postconcussion symptoms in blast-related mild traumatic brain injury.

Blast-related mild traumatic brain injury (mTBI) is a common injury among Iraq and Afghanistan military veterans due to the frequent use of improvised explosive devices. A significant minority of individuals with mTBI report chronic postconcussion symptoms (PCS), which include physical, emotional, and cognitive complaints. However, chronic PCS are nonspecific and are also associated with mental health disorders such as posttraumatic stress disorder (PTSD). Identifying the mechanisms that contribute to chronic PCS is particularly challenging in blast-related mTBI, where the incidence of comorbid PTSD is high. In this study, we examined whether blast-related mTBI is associated with diffuse white matter changes, and whether these neural changes are associated with chronic PCS. Ninety Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans were assigned to one of three groups including a blast-exposed no--TBI group, a blast-related mTBI without loss of consciousness (LOC) group (mTBI--LOC), and a blast-related mTBI with LOC group (mTBI + LOC). PCS were measured with the Rivermead Postconcussion Questionnaire. Results showed that participants in the mTBI + LOC group had more spatially heterogeneous white matter abnormalities than those in the no--TBI group. These white matter abnormalities were significantly associated with physical PCS severity even after accounting for PTSD symptoms, but not with cognitive or emotional PCS severity. A mediation analysis revealed that mTBI + LOC significantly influenced physical PCS severity through its effect on white matter integrity. These results suggest that white matter abnormalities are associated with chronic PCS independent of PTSD symptom severity and that these abnormalities are an important mechanism explaining the relationship between mTBI and chronic physical PCS.

Leukoencephalopathy in long term brain metastases survivors treated with radiosurgery.

Brain metastases (BM) develop in 10-30 % of patients. Stereotactic radiosurgery (SRS) was shown to improve local control, and performance status, in certain cohorts of brain metastasis patients. The cumulative neurocognitive effect of numerous SRS sessions remains unknown. Leukoencephalopathy is significant diffuse white matter changes and it usually implies a neurocognitive decline. We report patients with BM who survived >2 years after SRS. Clinical and treatment parameters were analyzed for development of leukoencephalopathy. Multiple parameters as well as leukoencephalopathy grade changes were recorded. The median clinical and radiological follow-up was 42 and 41 months (range 24–115 and 24–115) respectively. The cohort included 92 patients and 704 lesions. The most common malignancies were non-small cell lung carcinoma (44.5 % n = 41), breast adenocarcinoma (23.9 %, n = 22) and melanoma (16.3 %,n = 15). 27.6 % (n = 26) of patients underwent adjuvant WBRT. At last follow up, local tumor control was achieved in 76.3 % (n = 61) of patients and 71.8 % (n = 461) of lesions. Overall prevalence of leukoencephalopathy was 42, 60, 73 and 84 % at 1, 2, 3, and 4 years after SRS. Moderate-severe leukoencephalopathy development was related to an integral dose to skull >3 Joules (p = 0.012) at any radiosurgical treatment and prior WBRT (p<0.042). Leukoencephalopathy incidence was consistently higher in the WBRT + SRS group at each following year of survival from initial SRS. Long-term BM survivors treated with SRS are at progressive risk for developing leukoencephalopathy.Those with a higher BM burden, higher integral SRS dose to the skull, and treatment with WBRT are at increased risk of leukoencephalopathy.

Electromyoneurographic findings in patient with congenital muscular dystrophy

Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of inherited muscle disorders defined by early onset of hypotonia and muscle weakness. They are the second most common myopathic cause of floppy infant syndrome, following the group of congenital myopathies. The main CMD are classified by involved protein function and gene in which causative mutations occur. Merosin-negative muscle dystrophy is the most common CMD, characterized by early onset hypotonia, delayed motor milestones, contractures, normal cognitive abilities and diffuse brain white matter changes. Some forms of CMD are characterized by mental retardation, eye involvement, epileptic seizures and structural brain abnormalities. The diagnosis of CMD is based on clinical findings, elevated muscle enzymes, brain imaging, muscle biopsy histology and immunohistochemical staining and molecular genetic testing. The vast majority of patients have myopathic findings on electromyography (EMG). Slowed motor and sensory nerve conduction velocities could be found in patients with merosin deficiency. Electromyography has a significant role in the primary assessment of patients with muscle weakness. Myopathic EMG findings ruled out other causes of floppy infant syndrome and led to a muscle biopsy and focused genetic tests. An associated demyelinating neuropathy could focus the investigation on primary or secondary merosin deficit.

Post Flu Shot Confusion – think ADEM!

A 57-year-old Caucasian man with hypertension and diabetes presented with left arm weakness and headache for one day. He had an influenza vaccination 10 days prior to presentation. Computed tomography (CT) of the head showed a possible right MCA stroke. The next day he developed left hemiplegia. A repeat CT of the head exhibited a “mass like” effect in the right hemisphere. Magnetic resonance imaging (MRI) of the head showed a diffuse area of abnormal signals, involving both hemispheres, and diffuse white matter changes. His CSF showed WBC 4/mm3, RBC 1/mm3, glucose 97 mg/dl, and protein 96 mg/dl. He continued to deteriorate, developed encephalopathy, and had to be intubated. A repeat MRI of the head demonstrated extensive bilateral, poorly marginated white matter, and some grey matter involvement characteristic of acute disseminated encephalomyelitis (ADEM). He failed to respond to methylprednisolone 1 gram daily and was started on plasma exchange daily for 10 days. He started to improve after the second session. After five months he was essentially normal and had returned to work. This case demonstrates that routine vaccination can have important complications.

P119 – 2597: Neuroimaging findings of congenital CMV

Objective This report describes a case in which MRI pictures lead to diagnosis of Congenital CMV. Case 1: 8 months old infant was admitted to the Child Neurology department with muscle hypotonia, poor visual contact and developmental delay. She is 2nd child from 3rd pregnancy, child was born at term, with low birth weight. She had microcephaly, axial hypotonia and slight spasticity of the extremities with high tendon reflexes, and she was underweight. Bilateral sensorineural hearing loss was revealed by audiometry. MRI was done and delayed myelination, bilateral perisylvian polymicrogyria, and diffuse white matter changes were found in it. It was suspected CMV and then performed brain CT. Brain CTshowed periventricular calcifications. Conclusion The presence of the described MRI findings is an indication for CMV investigation. And intracranial calcification in addition to with such changes can be pattern recognition for Congenital CMV.

Dementia due to cerebral small vessel damage: Current ideas on its pathogenesis and therapy

Ever-increasing attention now focusses on dementia caused by small vessel damage when considering cerebrovascular disease leading to cognitive impairments (CIs). Stroke is one of the most important risk factors (RFs) of vascular CI, including vascular dementia. Experienced stroke increases thrice the risk of dementia. Diffuse changes in the cerebral white matter (leukoaraiosis) due to fluctuating blood pressure (BP) and cerebral small vessel damage in most cases play an important role in the genesis of vascular CIs. Executive dysfunctions frequently concurrent with delayed psychomotor speed are the leading clinical manifestations of subcortical vascular dementia. Severe memory impairments are not typical for subcortical dementia, its early stages in particular. The basis for the pathogenesis of CIs is the dissociation phenomenon that disrupts connections between the frontal lobes and subcortical structures and other cerebral cortical areas. Inadequate hypertension correction at a middle age is responsible for more than one fourth of cases of dementia developing in the elderly. The detection and further elimination of vascular RFs can reduce the risk of developing dementia in elderly and senile patients. Correction of elevated BP in the middle-aged is regarded as an effective method to prevent dementia in the future, but no premium is placed upon antihypertensive therapy in the elderly to lower elevated BP that is an inherent characteristic of this category of patients. Medications affecting RFs and those improving cerebral metabolism and blood flow, including nicergoline are widely used to treat PD.

Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain.

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.

White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

BackgroundMagnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM.MethodsWe used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles.ResultsThe degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P < 0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P < 0.01), with most prominent axonal abnormalities observed in the frontal WM (P < 0.05). The SIs of arterioles in CADASIL were increased by 25–45% throughout the regions assessed, with the highest change in the mid-frontal region (P = 0.000).ConclusionsOur results suggest disruption of either cortico-cortical or subcortical-cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures.

Depression in CADASIL patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary neurological disease accompanied by recurrent ischemic events, characterized by the presence of psychiatric disorders. The aim of this study was to examine the occurrence of depression and its severity among patients with CADASIL. Sixteen patients with diffuse white matter changes on MRI and clinical signs suggesting CADASIL were included in the study. Definitive diagnosis of CADASIL was obtained by electron microscopic analysis of skin biopsies. Testing of the patients? affective status was primarily devoted to detecting depression. Electron microscopic examinations of all skin biopsies revealed numerous granular osmiophilic material (GOM) deposits embedded into the basal lamina around altered or degenerated vascular smooth muscle cells (VSMCs). Clinical symptoms of depression were present in a great number of examined CADASIL patients. The frequency of depression was higher than previously reported. Psychiatric disturbances might also represent the onset of CADASIL, especially in young patients, and should be evaluated by differential diagnosis.

Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy phenotype in two siblings of a large family showing the same mutation

A 44-year-old Albanian male was consulted and diagnosed with dementia. His magnetic resonance imaging suggested diffuse white matter changes. The suspicion of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was raised, and a genetic analysis confirmed such a suspicion through uncovering a pathogenic mutation at the level of exon 4 (c.475C>T) of chromosome 19. The patient came from a large family of 13 children, all of whom underwent clinical, genetic, and imaging examination. The pathogenic mutation was found present only in his eldest sister (50 years old), and she presented also very suggestive signs of CADASIL in her respective imaging study, but without any clinically significant counterpart. All other siblings were free from clinical and radiological signs of the disorder. Our opinion was that we were dealing with a mutation showing a very low level of penetrance, with only two siblings affected in a large Albanian family with 13 children.

Disseminated Encephalomyelitis-Like Central Nervous System Neoplasm in Childhood

A malignant neoplasm in the central nervous system with diffuse white matter changes on magnetic resonance imaging (MRI) is rare in children. It could be misdiagnosed as acute disseminated encephalomyelitis. This report presents our experience based on 4 patients (3 male, 1 female; aged 7-13 years) whose MRI showed diffuse lesions in white matter and who were initially diagnosed with acute disseminated encephalomyelitis. All of the patients received corticosteroid therapy. After brain biopsy, the patients were diagnosed with gliomatosis cerebri, primitive neuroectodermal tumor and central nervous system lymphoma. We also provide literature reviews and discuss the differentiation of central nervous system neoplasm from acute disseminated encephalomyelitis.

Pediatric Herpes Simplex Virus Encephalitis

Knowledge on pediatric herpes simplex virus encephalitis is limited. Here we summarize 6 neonates and 32 children diagnosed by polymerase chain reaction (n = 37) or serological studies (n = 1), respectively. Diagnosis was difficult, as only 15 patients presented neurologic symptoms. Moreover, cerebrospinal fluid glucose, protein, and leukocytes were normal in 6 patients. Subsequently, all but 2 showed neurologic symptoms. Diffusion-weighted neuroimaging was the most sensitive early imaging method. Despite acyclovir treatment, 8 patients experienced early relapses, showing movement abnormalities, impaired vigilance, and seizures. Diffuse white matter changes, found in 3 of 5 relapse patients on neuroimaging, and a negative cerebrospinal fluid herpes simplex virus polymerase chain reaction suggested inflammatory processes. All relapse patients were again treated with acyclovir, and 3 responded to additional corticosteroid treatment. Whereas outcome after relapses was poor, overall outcome was good. No child died; 14 were asymptomatic at discharge, and neuroimaging remained normal in 7 of 30 patients studied.