Clinical diversity in acute necrotizing encephalopathy.

Acute necrotizing encephalopathy is a novel disease entity, proposed by Mizuguchi et al in 1995, that shows a characteristic selective and symmetric involvement of the thalamus, brain stem, and cerebellum. It usually leaves sequelae. The etiology of acute necrotizing encephalopathy is unknown. We describe here six patients aged 6 months to 5 years (four boys and two girls). Four cases were typical, and the patients' cranial computed tomographic scans and magnetic resonance imaging showed irreversible symmetric involvement of the thalamus, brain stem, and cerebellum. Three of the patients died, and one was left with severe sequelae. In the other two patients, who had selective reversible thalamic involvement, the disease was mild; one also showed transient unilateral thalamic involvement. These patients recovered completely. We consider the illness in these two patients to fit the criteria of the mild form of acute necrotizing encephalopathy. We believe that acute necrotizing encephalopathy has some clinical diversity, as is seen in other neurologic disorders, and that a mild form could exist.     

Hemi-meningitis with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare lymphoproliferative disorder. HLH may occur as a complication of Epstein-Barr virus (EBV), particularly in patients with immunodeficiencies. Herein, we describe a 16-year-old girl with neurological complications associated EBV-induced HLH. Her cerebral magnetic resonance imaging (MRI) showed contrast-enhanced axial T1-weighted images with enhancement of meningeal surface in the right hemisphere that was consistent with right hemi-meningitis. Hydrocephalus, dilated subdural spaces, delayed myelination, edema, diffuse parenchymal atrophy, calcifications, diffuse/patchy white matter abnormalities have all been previously described with HLH. To the best of our knowledge, this is the first case of hemi-meningitis associated with HLH. We suggest that clinicians should consider HLH with vascular disorders when they determine unilateral meningitis on a brain MRI.     

Primary angiitis of the central nervous system: report of five biopsy-confirmed cases from Colombia

INTRODUCTION: Primary (isolated) angiitis of the central nervous system (PACNS) is a rare cause of cerebrovascular disease (CVD), and few leptomeningeal and brain biopsy (LBB)-confirmed cases have been reported from South America. METHODS: We retrospectively reviewed charts of patients with diagnosis of cerebral angiitis admitted between March 1991 and July 2001 to a single university hospital in Medellin, Colombia. Patients with definitive diagnosis of PACNS by Alrawi et al.'s LBB criteria were selected. We excluded other causes of cerebral angiitis as well as cases without LBB confirmation. RESULTS: We report five patients, four men and one woman, with a mean age at onset of 24.4 years, and an average disease progression of 12.4 days. Four presented with headache and motor weakness, three had seizures, and two had alterations of consciousness. Cerebral MRI was abnormal in all five cases; brain CT in four, and cerebral angiography in two. The cerebrospinal fluid (CSF) was abnormal in two patients. Leptomeningeal and brain biopsies revealed mononuclear infiltration in the wall of small blood vessels in all. Three had concurrent meningeal and cerebral involvement, two had necrotizing angiitis, and one had vascular and encephalitic lesions. All received only steroid treatment; the 1-year follow-up revealed good prognosis without relapses. CONCLUSION: We report five biopsy-proven cases of PACNS from Colombia associated with neurological and neuroimaging abnormalities; these patients presented a mild inflammatory disease that was correlated with few CSF abnormalities and good response to single steroid treatment without relapses. Leptomeningeal and brain biopsy is mandatory for a definitive diagnosis.     

A case of acute encephalopathy with hemophagocytic lymphohistiocytosis and clonal T-cell expansion

We report on a 9-year-old boy who presented with acute encephalopathy and hemophagocytic lymphohistiocytosis (HLH). The patient was referred to our hospital because of fever, seizures, and decreased consciousness. He showed moderately elevated levels of proinflammatory cytokines in the cerebrospinal fluid and plasma, and clonal expansion of highly activated CD8⁺ T cells in the peripheral blood. These CD8⁺ T cells were found to be larger cells that stained positive for T-cell receptor Vβ13.6, and decreased shortly after steroid therapy. Our findings suggest that his acute encephalopathy was likely a clinical manifestation of HLH, and that immunophenotypic analysis may be helpful for early recognition of HLH in such rare encephalopathy.     

Acute encephalopathy as a primary manifestation of haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is characterized anatomically by an infiltration of multiple tissues with lymphocytes and haemophagocytic histiocytes. First symptoms are usually hepatosplenomegaly, pancytopenia, and intractable fever. Up to 73% of those with HLH develop CNS involvement during the disease course. The peculiarity of the two patients presented here, a 20-month-old Italian female and a 4-year-old Moroccan female, is that the initial presenting neurological symptoms mimicked an encephalitis, anticipating the typical systemic symptoms by 1 and 4 months. They developed progressive encephalopathy accompanied by status epilepticus, one child developed a secondary hydrocephalus. In both children it was not possible to detect an underlying infection or malignant disease and there were no other cases in the family that suggested a familial form of HLH. Diagnosis and initiation of treatment was delayed because of the initial encephalopathic clinical picture and the late onset of the typical systemic features. As early diagnosis allows better therapeutical approaches, haemophagocytic lymphohistiocytosis should be considered in children with persistent or progressive findings of encephalopathy, especially in the absence of identification of a plausible pathogen.     

Atypical clinical course in two patients with GNB1 variants who developed acute encephalopathy

IntroductionVariants in the GNB1 gene, which encodes the β1 subunit of a trimeric G protein, can cause moderate to severe psychomotor retardation. Acute encephalopathies have also been observed in patients with central nervous system abnormalities; however, severe neurological sequelae have not previously been reported.Case presentationsPatient 1 was a Japanese female with a de novo GNB1 variant (c.284 T > C). At 8 months old she contracted influenza A and developed generalized convulsions. In the acute phase, brain magnetic resonance imaging (MRI) findings indicated acute encephalopathy; diffuse cerebral atrophy was present 1 month later. Although multidisciplinary treatment was administered, she had severe neurological sequelae including spastic tetraplegia, severe intellectual disabilities, and refractory epilepsy. Patient 2 was a Japanese male with a de novo GNB1 variant (c.239 T > C). He experienced an unexplained respiratory arrest aged 17 years; refractory convulsions developed. Brain MRI at 1 month showed bilateral basal ganglia high intensities; at 3 months, diffuse cerebral cortex and white matter atrophy was observed. Despite multidisciplinary treatment, he developed severe spastic tetraplegia and mental regression.DiscussionWe report two patients with GNB1 variants who had acute lesions on brain MRI and unexpected disease courses. In such patients with acute neurological deterioration, multidisciplinary treatment is required; patients should also be carefully observed for progression to acute encephalopathy.     

Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with rarer neurological presentation. When this occurs, diagnosis may be delayed. This report aims to call attention to clinical, laboratory, and radiological features that should prompt the correct diagnosis. A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia. MRI showed a diffuse tumor-like swelling of the cerebellum with tonsillar herniation and patchy white matter post-contrast enhancement. Regression of swelling with steroids ruled out glioma and medulloblastoma, and brain lymphoma was considered. Diagnosis of HLH was reached 2 months after onset when uncontrolled fever and severe elevation of liver enzymes occurred. Two bone marrow biopsies were needed to demonstrate hemophagocytosis. Familial HLH was confirmed by perforin gene mutations. Bone marrow transplantation was performed. The early diagnosis of HLH may be life saving. Awareness of the disease is necessary to investigate its characteristic findings, thus avoiding a delay in diagnosis.     

Recurrent acute necrotizing encephalopathy in a boy with RANBP2 mutation and thermolabile CPT2 variant: The first case of ANE1 in Japan

BackgroundAcute necrotizing encephalopathy (ANE) is a severe encephalopathy associated with acute viral infection. While most ANE cases are sporadic, pathogenic variants in the gene RAN binding protein 2 (RANBP2) have been identified as a major cause of familial or recurrent ANE (ANE1). Although sporadic ANE predominantly affects Asian children, ANE1 is very rare in east Asia.Case reportA 1-year-7-month-old boy, born to unrelated Japanese parents, presented with a seizure and impaired consciousness after 3 days of fever. Brain magnetic resonance imaging (MRI) showed a characteristic involvement of the bilateral thalami, external capsules, insular cortices, and brainstem, suggesting ANE. He received intravenous steroids. Two months later, he had another episode of acute encephalopathy during respiratory syncytial virus infection, from which he recovered relatively well. The recurrent encephalopathic episodes and the characteristic MRI suggested ANE1. Genetic analyses revealed two variants: a rare heterozygous missense variant of RANBP2 [c.1754C>T; p.Thr585Met], and a thermolabile polymorphism in carnitine palmitoyltransferase 2 (CPT2) [c. 1055T>G; p.Phe352Cys].ConclusionThis is the first case of recurrent ANE with an RANBP2 mutation in Japan. The patient also harbored a CPT2 polymorphism that is linked to acute encephalopathy in Japanese patients. Thus, he had a genetic background with two susceptibility variants for acute encephalopathy, RANBP2 (frequent in the Caucasians), and CPT2 (frequent in the Japanese). Further studies are needed to fully discover the genetic predisposition to familial or recurrent ANE in the Asian population.     

Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum

BackgroundPyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6′ carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported.Methods and ResultsWe present a phenotypic spectrum of antiquitin deficiency based on a literature review (2006 to 2015) of reports (n = 49) describing the clinical presentation of confirmed patients (n > 200) and a further six patient vignettes. Possible presentations include perinatal asphyxia; neonatal withdrawal syndrome; sepsis; enterocolitis; hypoglycemia; neuroimaging abnormalities (corpus callosum and cerebellar abnormalities, hemorrhage, white matter lesions); biochemical abnormalities (lactic acidosis, electrolyte disturbances, neurotransmitter abnormalities); and seizure response to pyridoxine, pyridoxal-phosphate, and folinic acid dietary interventions.DiscussionThe phenotypic spectrum of pyridoxine-dependent epilepsy is wide, including a myriad of neurological and systemic symptoms. Its hallmark feature is refractory seizures during the first year of life. Given its amenability to treatment with lysine-lowering strategies in addition to pyridoxine supplementation for optimal seizure control and developmental outcomes, early diagnosis of pyridoxine-dependent epilepsy is essential. All infants presenting with unexplained seizures should be screened for antiquitin deficiency by determination of α-aminoadipic semialdehyde/pyrroline 6′ carboxylate (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis.     

An unusual case of insomnia associated with Whipple encephalopathy: first case reported from Greece

Abstract Whipple disease is a relapsing systemic illness caused by Tropheryma whippelii. Central nervous system involvement occurs in 5%–40% of all patients. Hypothalamic manifestations occur in 31% of Whipple encephalopathy, including polydipsia, hyperphagia, change in libido and insomnia. We report a case of a 48–year–old man with severe insomnia, depression, dementia, dysarthria, myoclonic movements of the limbs and ophthalmoplegia. The diagnosis of Whipple encephalopathy was confirmed by PCR analysis of blood and faeces. He received a full dose of antibiotic treatment. Despite clinical improvement, resolution of the lesions detected in MRI scan of the brain and negative results of the PCR in blood, faeces and cerebrospinal fluid six months later, insomnia persisted and finally subsided after the administration of carbamazepine (600 mg/day). Our case supports the finding that carbamazepine might be useful in the treatment of insomnia associated with Whipple encephalopathy.     

Acute necrotizing encephalopathy associated with enterovirus infection

Acute necrotizing encephalopathy is a rare, clinically distinct entity of acute encephalopathy triggered by acute febrile diseases, mostly viral infections. It is postulated to arise from uncontrolled cytokine release during a febrile illness, and is most often seen in East Asia. We describe a rare Saudi patient of acute necrotizing encephalopathy attributable to enterovirus in a 4 years and 6 months old girl. A work-up revealed elevations in serum and cerebrospinal fluid interleukin-6 and tumor necrosis factor-α. The outcome on intravenous pulse methylprednisolone was good. This case is the first, to the best of our knowledge, of acute necrotizing encephalopathy reported from Saudi Arabia with a good outcome despite severe magnetic resonance imaging findings and delay in the steroid treatment.     

Risk Factors for Intraventricular Hemorrhage in Term Asphyxiated Newborns Treated With Hypothermia

BackgroundIntraventricular hemorrhage is rare in term newborns. Severe asphyxia is recognized as one of the risk factors of intraventricular hemorrhage in these newborns. Therapeutic hypothermia, which is the only available treatment for the limitation of brain injury in term asphyxiated newborns, may cause fluctuations of cerebral blood flow, possibly placing the newborn more at risk for intraventricular hemorrhage. The literature regarding the incidence of intraventricular hemorrhage in the context of neonatal hypoxic-ischemic encephalopathy and hypothermia is sparse.MethodsWe present a clinical observation and review the literature regarding the risk factors for intraventricular hemorrhage in term asphyxiated newborns treated with hypothermia.ResultsWe describe the clinical course of a term newborn with severe hypoxic-ischemic encephalopathy who developed significant intraventricular hemorrhage during the rewarming period after the 72-hour hypothermia.ConclusionThis newborn presented several risk factors for intraventricular hemorrhage, including severe asphyxia, hemodynamic instability, hemostasis disturbances, instrument delivery, venous sinus thrombosis, and hypoglycemia. Hypothermia and rewarming also may have contributed by causing fluctuations in cerebral blood flow.     

Central Nervous System Involvement in Hemophagocytic Lymphohistiocytosis: A Single-Center Experience

BackgroundHemophagocytic lymphohistiocytosis is a rare multisystem disorder characterized by proliferation and diffuse infiltration multiple organs with histiocytes, including the central nervous system.PATIENTS and MethodsThirty children diagnosed with hemophagocytic lymphohistiocytosis between 1997 and 2010 were reviewed and analyzed. Central nervous system disease involvement was defined as the presence of neurological symptoms and signs or elevated values of cerebrospinal fluid cells and/or proteins.ResultsAmong the 30 patients, 17 (56%) had central nervous system involvement. Fourteen patients (46%) presented with neurological symptoms including seizures, irritability, bulging fontanelle, cranial nerve palsy, or disturbance of consciousness, whereas the remaining three patients developed central nervous system symptoms during the course of the disease. Seventeen patients (56%) had cerebrospinal fluid abnormalities. Neuroradiological studies were performed in nine patients. The most common findings were edema, atrophy, subcortical necrosis, and high signal intensity on T2-weighted magnetic resonance imaging. All patients were treated according to the Hemophagocytic Lymphohistiocytosis-94 and Hemophagocytic Lymphohistiocytosis-2004 protocols. Patients with central nervous system involvement had greater mortality. In prediction of the outcome, the cutoff value for cerebrospinal fluid protein was 470 mg/L. The most common neurological sequela was psychomotor delay.ConclusionCentral nervous system involvement in hemophagocytic lymphohistiocytosis is common and is associated with poor outcome.     

Two Cases of Hypertensive Encephalopathy Involving the Brainstem

Hypertensive encephalopathy is a medical emergency whose clinical manifestations are usually associated with bilateral parieto-occipital lesions. Predominant brainstem edema without accompanying occipital lesions is rare in hypertensive encephalopathy and usually occurs in patients with secondary hypertension. We describe the clinical and radiological features of two patients with reversible hypertensive brainstem encephalopathy. Both patients had chronic renal failure, but the extensive neuroimaging abnormalities revealed few clinical features of brainstem involvement. The clinical findings and neuroimaging abnormalities resolved once the hypertension was treated.     

A Case of Adult Influenza A Virus–Associated Encephalitis: Magnetic Resonance Imaging Findings

A 27-year-old man presented with fever, convulsive seizure, and sudden impairment of consciousness. Magnetic resonance imaging (MRI) abnormalities were found in the bilateral thalami, including the brain stem and white matter. The possibility of a previous influenza A virus infection was considered, and cerebrospinal fluid cells and interleukin-6 were elevated. The MRI findings closely resembled those found in cases of childhood acute necrotizing encephalopathy (ANE). The present case suggests that adult influenza A virus-associated encephalitis/encephalopathy or ANE can occur during winter influenza epidemics.     

Granulomatous Herpes Simplex Encephalitis in an Infant With Multicystic Encephalopathy: A Distinct Clinicopathologic Entity?

BackgroundHerpes simplex virus encephalitis can manifest as a range of clinical presentations including classic adult, neonatal, and biphasic chronic-granulomatous herpes encephalitis.MethodWe report an infant with granulomatous herpes simplex virus type 2 encephalitis with a subacute course and multicystic encephalopathy.CaseA 2-month-old girl presented with lethargy and hypothermia. Computed tomography scan of the head showed multicystic encephalopathy and calcifications. Cerebrospinal fluid analysis by polymerase chain reaction testing for herpes simplex virus 1 and 2, enterovirus, and cytomegalovirus was negative. Normal cerebrospinal fluid interferon-α levels argued against Aicardi-Goutières syndrome. The patient died 2 weeks after presentation. At autopsy, multicystic encephalopathy was confirmed with bilateral gliosis, granulomatous inflammation with multinucleated giant cells, and calcifications. Bilateral healing necrotizing retinitis suggested a viral etiology, but retina and brain were free of viral inclusions and immunohistochemically negative for herpes simplex virus-2 and cytomegalovirus. However, polymerase chain reaction analysis showed herpes simplex virus-2 DNA in four cerebral paraffin blocks. Subsequent repeat testing of the initial cerebrospinal fluid sample using a different polymerase chain reaction assay was weakly positive for herpes simplex virus-2 DNA.ConclusionGranulomatous herpes simplex virus encephalitis in infants can present with subacute course and result in multicystic encephalopathy with mineralization and minimal cerebrospinal fluid herpes simplex virus DNA load. Infectious etiologies should be carefully investigated in the differential diagnosis of multicystic encephalopathy with mineralization, in particular if multinucleated giant cells are present.     

De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum

BackgroundHeterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 protein, an essential subunit of the DNA-dependent RNA polymerase II.Case presentationWe investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks.ConclusionThis case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.     

Spontaneous and reflex movements after diagnosis of clinical brain death: A lesson from acute encephalopathy

BackgroundOrgan transplantation after brain death (BD) of the donor has been promoted in many countries as an established medical treatment. However, some problems with brain-dead organ transplantation have been reported. For example, there is no evidence as to the optimal observation period for a diagnosis and no evidence to support the interpretation of the various body movements observed after the determination of BD.Case reportA previously healthy 17-month-old girl with severe febrile convulsive status was transferred to our intensive care unit. The convulsions were refractory and the patient required respiratory management due to whole brain edema on head CT. Later she was diagnosed with acute encephalopathy. The patient showed a flat EEG, no responses on auditory brainstem responses (ABR), and loss of brainstem reflexes on repeated daily examinations. No apnea test was performed. Based on the diagnosis of clinical BD, coordinator of Japan Organ Transplant Network explained about organ donation on the 17th day of the disease. Subsequently, the family responded that they could not consent to organ donation, and the patient did not proceed to the legal BD determination. Around five weeks after the onset, spontaneous body movements began to appear, as not only the spinal reflexes but also the brainstem involvement.ConclusionThe pathophysiology of acute encephalopathy is largely unknown, and it is difficult to determine the observation period necessary for BD determination. What we have learned from this case is that clinical BD remains ambiguous and cannot be confirmed even with a thorough neurological examination, EEG, and ABR.     

Demyelinating peripheral neuropathy associated with hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study

We report the case of an 11-year-old male who developed subacute diffuse polyradiculoneuropathy, associated with digestive symptoms and Epstein-Barr virus infection. Parental consanguinity was present. The laboratory findings including bone marrow smear were consistent with hemophagocytic lymphohistiocytosis (HLH). Electrophysiological study of peripheral nerves revealed an intense and diffuse demyelinating process. The histological nerve lesions were severe and purely demyelinating. Most axons were intact. There was a diffuse infiltration of the nerve parenchyma by mononuclear cells. Immuno-electron microscopic study evidenced entry of macrophages into Schwann cell cytoplasm with dissociation of myelin sheaths. This boy died several months after the onset of the neuropathic symptoms. HLH is a rare genetic or acquired disorder in childhood characterized by abnormal immune activation, which induces an uncontrolled inflammatory response with sustained hyperactivation of T lymphocytes and macrophages. Only very rare cases of peripheral nerve involvement have been described in HLH. This is the first case showing that peripheral nerves, as other viscera, may be destroyed by the macrophagic infiltration, which characterizes HLH.