Diffuse Encephalopathy Research Articles

Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children

BackgroundPlasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention.MethodsPostmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2–4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-γ, TNF-α, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-β1, PDGF bb and VEGF) were measured and the results compared between the 3 groups.ResultsAfter Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1β, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups.ConclusionThe parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1β, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.

L-2-Hydroxyglutaric aciduria presenting with severe autistic features

l-2-Hydroxyglutaric aciduria ( l-2-HGA) is an autosomal recessive neurometabolic disorder characterized by psychomotor delay, ataxia, macrocephaly and typical neuroradiological findings of subcortical leucoencephalopathy. Recently, the disease causing gene has been discovered ( L2HGDH) encoding l-2-hydroxyglutarate dehydrogenase. We present a 3-year-old boy with l-2-HGA, who demonstrated macrocephaly, noted already in utero with ultrasound. Cranial MRI demonstrated diffuse subcortical encephalopathy with increased signal of the subcortical white matter. Subsequent metabolic screening revealed increased levels of l-2-HGA, and genomic DNA analysis demonstrated two missense mutations in l-2-HGDG. Patient’s further motor development was mildly impaired, whilst his speech development was profoundly impaired (first words at the age of 2 years). Since the age of 2 years he started demonstrating autistic repetitive behaviors and movements, increasing aloofness to his environment and limitations in the variety of spontaneous activity (CARS score: 44/60-severe autism). Autism has not so far been described in l-2-HGA and may be considered as an additional feature of the phenotypic spectrum.

Pediatric Epilepsy Evaluations From the Prenatal Perspective

Prenatal contributions to childhood epilepsy include malformations and acquired injuries, which can occur from conception and throughout gestation. Five case histories from the Pediatric Epilepsy Service are discussed that exemplify maternal, fetal, and placental conditions that contribute to childhood epilepsy. Two full-term neonates presented with neonatal seizures, with or without accompanying encephalopathy. Placental pathology suggested antepartum maternal-placental diseases that caused or contributed to their brain disorders. Two children presented as preterm infants with systemic organ system diseases that also implicated brain injury. One child had a complicated maternal history with both genetic and acquired illnesses. Two children required epilepsy surgery, with improved seizure control despite persistent neurocognitive and neurobehavioral deficits related to diffuse encephalopathies. Dual pathology should include prenatal contributions to childhood epilepsy on both a genetic and acquired basis. Epileptologists should consider an ontogenetic approach to study the epileptic condition from a fetal neurology perspective.

Incorporating Abbreviated EEGs in the Initial Workup of Patients Who Present to the Emergency Room With Mental Status Changes of Unknown Etiology

Patients frequently present to the emergency room (ER) with mental status changes without obvious cause. The EEG is underused in this population. The authors investigated whether an abbreviated EEG (AbEEG) can be incorporated in the early evaluation of these patients to provide useful information. A 5-minute AbEEG was performed using a preformed electrode placement system on 25 patients who presented to the ER with mental status changes of unknown cause. AbEEG findings were categorized as normal, showing diffuse abnormalities, focal abnormalities, electrographic seizures, or uninterpretable. Using retrospective chart review, the authors determined if the cause of mental status change was a diffuse encephalopathy or a nonneurologic event (DENNE), a focal brain abnormality, nonconvulsive status epilepticus (NCSE), psychogenic, or unknown, and if particular AbEEG findings were associated with specific causes of altered sensorium. The AbEEG identified NCSE in two patients who presented with new-onset seizures. The presence of diffuse slowing on the AbEEG was highly suggestive of mental status changes due to DENNE. AbEEGs can be successfully incorporated in the early evaluation of patients who present to the ER with mental status changes of unknown cause and provide useful information in this setting.

Trends in neurological complications of endocarditis

Neurological complications (NCs) are a major cause of morbidity and mortality in patients with infectious endocarditis (IE). The frequency of these complications has been found to remain constant since the preantibiotic era despite profound epidemiological changes and therapeutic advances. We have reviewed retrospectively all the cases of IE attended at a single institution between 1985 and 2003, aiming to study the clinical characteristics of the NCs, and to analyse possible temporal trends in their frequency. Among 550 patients with IE, 71 (13%) suffered NCs. NCs presented more frequently in native (NVE) and prosthetic (PVE) valve endocarditis (17% and 20%, respectively) than in endocarditis associated with drug addiction (IDU-NVE) or pacemeker (6% and 9%, respectively). Cerebrovascular disorders were the most frequent NCs (60% of the patients had ischemic events and 21% had haemorrhages). Meningitis and cerebral abscess occurred in 16% and 3% of patients with NCs, respectively, and diffuse encephalopathy in 13%. Staphylococus aureus infection was the only factor associated with NCs, but only in NVE. During the study period there was a trend for increasing frequency of NCs in IE patients, probably associated to several factors: a decrease in IDUNVE, an increase in more aggressive nosocomial acquired NVE, and an increase in NVE caused by S. aureus. Mortality among patients with NCs (34%) was significantly higher than in IE patients without them (11%). During the study period mortality increased in patients with NVE and NCs.

Post-malaria neurological syndrome: clinical and laboratory findings in one patient

Post-malaria neurological syndrome (PMNS) is a rare complication of malaria. It follows recovery from an episode of Plasmodium falciparum malaria and is characterised by symptoms and signs of encephalopathy. Patients usually improve without any specific treatment. The pathogenesis is unknown, but it is probably immunologically mediated. The objective of this case study is to describe the first Italian patient with PMNS. A 60-year-old Italian man developed acute P. falciparum malaria after a stay in French Guinea. Twenty days after recovering from malaria, he became confused, developed generalised weakness, limb tremors, shivering and dizziness. These symptoms continued for three days, then resolved spontaneously. Neuroimaging was normal. Cerebrospinal fluid analysis revealed breakdown of the blood/brain barrier, without oligoclonal bands and normal IgG index. Our patient presented a mild diffuse encephalopathy suggestive of a generic activation of the immune system without any specific reaction against antigens within the CNS.

Neurological complications of liver transplantation in pediatric patients: A single center experience

Neurologic complications (NCs) are a significant cause of morbidity and mortality in patients who undergo liver transplantation (LT). The aim of this study was to evaluate the incidence and type of NCs and associated factors in pediatric LT patients. We retrospectively reviewed NCs in the medical records of 40 consecutive infants, children, and adolescents who underwent LT at our institution. The subjects consisted of 23 boys and 17 girls (median age, 8.5 +/- 0.85 yr; range, 11 months to 17 yr). The indications for LT were Wilson's disease in 10 patients, fulminant hepatic failure (FHF) in nine, and other types of chronic liver disease in 21. NCs were found in 14 patients (35%). Those 14 individuals experienced a total of 16 episodes of NCs (two separate episodes in two of the patients). The most common NCs were seizure (seven episodes in six patients) and posterior leukoencephalopathy syndrome (PLES; five episodes in four patients). Seizure was the presenting symptom in three episodes of PLES. Two episodes of diffuse encephalopathy were observed in two patients, and two episodes of psychiatric symptoms occurred in two patients. We also noted one episode of tremor in one patient, one episode of acute dystonic reaction in one patient, and one episode of headache in one patient. Patients with Wilson's disease had a higher incidence of NCs (60%) than did patients without Wilson's disease (26.7%); however, this difference was not significant. The incidence of NCs was 44% in patients with FHF and 35% in those without FHF. That difference also was not significant. Immunosuppressive agents were the primary cause of 13 of the 16 episodes of NC. Uremia with hypertension, hypoxia, and hypomagnesemia caused one neurologic episode each. NCs, which are frequent in the first 30 days after pediatric LT, did not affect survival in this group. NCs were reversed by the discontinuation or reduction of immunosuppressive agents in 12 episodes, correction of hypomagnesemia and the reduction of immunosuppressive agents in one episode, and the correction of uremia and hypertension in one episode. Refractory epilepsy developed in one patient, and death unrelated to NCs occurred in one. The mortality rate was 7.1% (n = 1) in patients with NCs and 15.4% (n = 4) in those without NCs (p = 0.64). NCs are an important complication after LT. It is essential that each transplantation team collaborate with pediatric neurologists to ensure the rapid and accurate diagnosis of NCs in infants, children, and adolescents after LT and to prevent the delay of appropriate treatment.

Multiple independent spike foci and epilepsy, with special reference to a new epileptic syndrome of “severe epilepsy with multiple independent spike foci”

Background Markand and Blume first realized the specificity of the EEG pattern of multiple independent spike foci (MISF) in the late 1970s; its close relation with hypsarrhythmia and slow spike-waves, extensive bilateral brain lesion, and intractable seizures. But they did not recognize it as an epileptic syndrome. On the other hand, the authors had been taken notice of severe epilepsy with MISF (SE-MISF) as a peculiar clinico-electrical entity showing “generalized seizures”, and pointed out its close relation to Lennox–Gastaut syndrome (LGS) from the long-term follow-up of LGS. Summary points SE-MISF is characterized by (1) interictal EEG showing multiple independent spike foci (three or more foci in both hemisphere, i.e. at least one in each hemisphere) and diffuse slowing of the background activity. Diffuse epileptic discharges are rare. (2) The main seizure type is frequent generalized minor seizures, often tonic spasms. (3) Mutual transition is often observed between the age-dependent epileptic encephalopathies, i.e. Ohtahara syndrome, West syndrome and LGS. (4) The age at epilepsy onset is early, but the onset of SE-MISF is variable. (5) It is often associated with mental retardation and neurological abnormalities, usually severe. (6) Etiology is variable and largely nonspecific, including prenatal, perinatal, and postnatal cerebral pathologies. (7) Prognoses for seizures and psychomotor development are poor. Seizures are very intractable and may cause psychomotor deterioration. Conclusion SE-MISF may be classified into symptomatic generalized epilepsy, namely a diffuse encephalopathy with mutual transition between other age-dependent epileptic encephalopathies. This characteristic entity may be acknowledged as a new epileptic syndrome.

Cerebral malaria owing toPlasmodium vivax: case report

Cerebral malaria is a diffuse encephalopathy associated with seizures and status epilepticus which can occur in up to one-third of children with severe malaria, particularly that caused by Plasmodium falciparum. We report a unique case of P. vivax infection complicated by status epilepticus. A 4-year-old boy was admitted to the emergency outpatient clinic with intractable seizures for the previous hour. During resuscitation, two episodes of left-focal tonic convulsions occurred and he received phenytoin. Because of a history of P. vivax infection in the family 3 months previously, a blood slide for malaria was undertaken. Thin blood smears demonstrated P. vivax. He was treated with chloroquine and primaquine. An initial EEG was normal but after 3 months of follow-up a second EEG showed generalised epileptic activity. Rarely, cerebral malaria is a presenting complication or occurs during the course of P. vivax infection. In endemic areas such as Turkey, the possibility of cerebral malaria should be considered.

OCTOBER 2004: A 49-YEAR-OLD MAN WITH PROGRESSIVE DEMENTIA

October 2004. A 49-year-old right-handed man developed progressive cognitive difficulties over a 4-month period. There was impairment in recent memory, calculations and language. He also developed fatigue, weight loss, gait imbalance and urinary incontinence. Past history included transfusion-associated Hepatitis C. Neurologic exam showed mild dysarthria, dysnomia, left sided neglect, bilateral Babinski signs, and a prominent grasp reflex. Laboratory testing provided no positive etiologic data. An EEG showed generalized intermittent slowing suggestive of a diffuse encephalopathy and decreased background in the right hemisphere, suggestive of a structural lesion. MRI showed multiple areas of high signal on FLAIR imaging and patchy enhancement. FDG-PET showed multi-focal areas of increased uptake, correlating with the abnormal areas on MRI, on a background of decreased uptake. A 4-vessel cerebral angiogram showed no abnormalities. A brain biopsy showed diffuse infiltrates of large malignant cells that were immunoreactive with antibodies to CD20, diagnostic of diffuse large B cell lymphoma. In summary, the clinical presentation suggested bilateral hemispheric involvement, which was supported by physical examination, EEG, MRI, and PET scans. The differential diagnosis for this presentation is limited to demyelinating disease such as multiple sclerosis, vascular dementia, and infiltrating neoplasm such as glioblastoma multiforme or lymphoma. Diagnosis was made by morphologic and immunohistochemical analysis of brain tissue.

Japanese Encephalitis, Singapore

Japanese Encephalitis, Singapore

Neurobehavioral and clinical effects in workers exposed to CS 2

Objectives Diffuse vascular encephalopathy, parkinsonism and peripheral polyneuropathy (PNP) due to CS 2 exposure are known since long. Data concerning low exposure are sparse. The current study aimed to evaluate whether the decrease of exposure below the threshold limit value (TLV) of 31 mg/m 3 results in an absence of neurological health effects using the same health outcomes as in the first study [Vanhoorne et al., 1995. An epidemiologic study of the effects of carbon disulfide on the peripheral nerves. Int. J. Occup. Environ. Health 1, 295–302]. Methods The study was conducted in a group of workers of a viscose rayon plant and a control group (CG, n = 66 ). The exposed group was divided into two groups, according to the average CS 2 exposure being below (EG1; n = 60 ) or above 31 mg/m 3 (EG2; n = 25 ). If the current TLV seemed insufficient to prevent effects, the analysis was repeated with three subgroups (⩽10, >10 to ⩽30, >30 mg/m 3) to estimate the NOEL. Every participant filled in the neurotoxicity symptom checklist (NSC-60) and the Q16. Clinical neurological examination, computer-assisted neurobehavioral tests (NES) and neurophysiological examinations (nerve conduction velocities and electromyography (EMG)) were performed. Results Sensorimotor complaints (NSC-60) were significantly worse in both EG1 and EG2 compared to CG ( p = 0.032 ) and both exposure groups had a higher proportion of positional tremor compared with CG ( p = 0.046 ). Finger tapping in the dominant and non-dominant hand (NES) was worse in EG1 and EG2 compared with CG (both p < 0.001 ). A significant increase in sural nerve SCV, a significant decrease in sural nerve SNAP amplitude and duration and sympathic skin response (SSR) amplitude, and higher prevalence of EMG abnormalities and PNP was also found in both EG1 and EG2 ( p < 0.003 ). All effects remained significant after controlling for possible confounding factors. Further analysis suggested that even average CS 2 exposures of ⩽10 mg/m 3 could still cause effects on positional tremor, finger tapping dominant and non-dominant hand, sural nerve amplitude, SSR amplitude and EMG abnormalities. Conclusions An excess of psychomotor slowing, tremor and PNP was found in workers on average exposed to CS 2 concentrations below 31 mg/m 3. Data suggest that even average exposures as low as ⩽10 mg/m 3 can cause the deleterious effects. This indicates that the current TLV insufficiently protects against neurological effects and, as a consequence, should be lowered.

Practical Management Issues for Idiopathic Generalized Epilepsies

The idiopathic generalized epilepsies (IGE) are a group of epilepsies that are genetically determined, have no structural or anatomic cause, and usually begin early in life. Neurologic examination, intelligence, and imaging studies are normal, and EEG shows only epileptiform abnormalities (i.e., no abnormal slow activity or evidence for diffuse encephalopathy). In some IGE, the genetic substrate has been identified, whereas in most, it remains unknown. Depending on the age at onset and predominant seizure type, individual subtypes of IGE (syndromes) are defined. However, overall, there are more similarities than there are differences among the various subtypes, and the IGE are best viewed as a spectrum or continuum of conditions. In general, IGE respond to treatment, with 80-90% becoming fully controlled. However, not all antiepileptic drugs (AED) are equally effective in IGE. Some AED are ill advised because they either do not work or exacerbate seizure types other than generalized tonic-clonic (GTC) seizures, that is, absence and myoclonic seizures. These include carbamazepine, oxcarbazepine, phenytoin, gabapentin, and tiagabine. Their use is the main cause of "pseudo-intractability," and at least in the United States where PHT and CBZ are the most commonly used AEDs, patients with IGE are often on inadequate medications. For patients with clear IGE, the drug of choice is generally valproic acid because it effectively controls absence myoclonic seizures and GTC seizures. Second-line drugs (when first-line drugs fail or are not tolerated) may include benzodiazepines, but the use of second-line drugs is evolving rapidly. Some of the newer AEDs are considered broad spectrum, meaning that they work in IGE and focal epilepsies, although the evidence is largely preliminary at this point. These newer AEDs include lamotrigine, topiramate, levetiracetam, and zonisamide.

Neurological complications of HIV

Abstract Before HAART about 10% of AIDS patients in developed countries presented with neurological opportunistic infections and malignancies, but these presentations are now less common. Peripheral neuropathy is still common as a complication of therapy. Patients with advanced HIV infection may present with diffuse encephalopathy directly as a result of HIV infection itself (AIDS dementia). Less common causes of this clinical picture include cytomegalovirus, herpes simplex virus (HSV) and rarely toxoplasmosis. Focal cerebral disease is commonly caused by toxoplasmosis, cerebral lymphoma or progressive multifocal leucoencephalopathy. Characteristic CT and MRI appearances usually allow these to be distinguished. In the case of a presumptive diagnosis of toxoplasmosis a therapeutic trial of anti-toxoplasma therapy should be given before brain biopsy is considered. Rare causes of focal cerebral lesions include tuberculosis, cryptococcosis, candidosis, HSV and varicella-zoster virus. Mild CSF lymphocytosis and moderate elevation of CSF protein are common in HIV patients at all stages of infection. Bacterial meningitis is uncommon, but cryptococcal meningitis is common, particularly in patients from Africa.

Porphyria Presenting as Diffuse Encephalopathy

An 18-year-old female presenting with seizures, myalgias, abdominal pain, headache and vomiting had multiple large contrast-enhancing white matter lesions on MRI and was diagnosed with acute intermittent porphyria (AIP), in a report from the Department of Neurology, Mayo Clinic, Rochester, MN.

Specific Kinetic Alterations of Human CaV2.1 Calcium Channels Produced by Mutation S218L Causing Familial Hemiplegic Migraine and Delayed Cerebral Edema and Coma after Minor Head Trauma

Mutation S218L in the Ca(V)2.1 alpha(1) subunit of P/Q-type Ca(2+) channels produces a severe clinical phenotype in which typical attacks of familial hemiplegic migraine (FHM) triggered by minor head trauma are followed, after a lucid interval, by deep (even fatal) coma and long lasting severe cerebral edema. We investigated the functional consequences of this mutation on human Ca(V)2.1 channels expressed in human embryonic kidney 293 cells and in neurons from Ca(V)2.1 alpha(1)(-/-) mice by combining single channel and whole cell patch clamp recordings. Mutation S218L produced a shift to lower voltages of the single channel activation curve and a consequent increase of both single channel and whole cell Ba(2+) influx in both neurons and human embryonic kidney 293 cells. Compared with the other FHM-1 mutants, the S218L shows one of the largest gains of function, especially for small depolarizations, which are insufficient to open the wild-type channel. S218L channels open at voltages close to the resting potential of many neurons. Moreover, the S218L mutation has unique effects on the kinetics of inactivation of the channel because it introduces a large component of current that inactivates very slowly, and it increases the rate of recovery from inactivation. During long depolarizations at voltages that are attained during cortical spreading depression, the extent of inactivation of the S218L channel is considerably smaller than that of the wild-type channel. We discuss how the unique combination of a particularly slow inactivation during cortical spreading depression and a particularly low threshold of channel activation might lead to delayed severe cerebral edema and coma after minor head trauma.

Acute intermittent porphyria presenting as a diffuse encephalopathy

Although acute intermittent porphyria presents with dramatic neurological findings, the diagnosis is difficult. An 18-year-old woman had a clinical picture of porphyric encephalopathy. Magnetic resonance (MR) imaging demonstrated multiple large contrast-enhancing subcortical white matter lesions, which regressed with glucose and hematin infusions. Diffusion-weighted MR imaging was normal, and MR spectroscopy excluded acute demyelination or tissue necrosis. MR findings of acute intermittent porphyria can differ from those in posterior reversible encephalopathy syndrome by virtue of intense contrast enhancement. Because diffusion-weighted MR imaging and spectroscopy were normal, the lesions are likely caused by reversible vasogenic edema and transient breakdown of the blood-brain barrier.

Infections and Stroke

We will review cerebrovascular complications of infectious diseases of the CNS. The emphasis will be on common infections causing stroke, including pyogenic meningitis, infective endocarditis, tuberculosis, leptospirosis, syphilis, as well as fungal and parasitic diseases. Most of these conditions cause stroke through a mechanism of angiitis, which is an inflammation of the vessel wall induced by the presence of microorganisms within the CNS. A stroke may occur as the primary or sole manifestation of the infectious disease or may present in the setting of a diffuse encephalopathy. Infection-related strokes may be ischemic or hemorrhagic and range in severity from asymptomatic to fatal. Precise knowledge of the spectrum of these conditions is important to direct prompt therapy to reduce the risk of further vascular damage.

EMPTY SELLA SYNDROME, PANHYPOPITUITARISM, AND DIABETES INSIPIDUS

We present an 18-month-old girl with short stature, obesity, panhypopituitarism, diabetes insipidus, and visual defects. Postmortem examination revealed brain atrophy due to a diffuse encephalopathy, numerous calcified neurons in cerebral cortex, deep telencephalic and diencephalic nuclei, diffuse neuronal necrosis in hypothalamic nuclei, moderate atrophy of optic nerves, very thin hypophyseal stalk, and empty sella with the hypophysis compressed to the dorsal aspect of the concavity. Our hypothesis is that the presence of an empty sella in a child with hypophyseal-hypothalamic abnormalities should alert physicians to the existence of hypothalamic lesions secondary to a perinatal insult. We discuss the possible pathogenesis of these findings as well as lines of evidence available in the literature.

Metronidazole-induced encephalopathy

We report the clinical, neuropsychological, and neuroimaging findings of two patients of diffuse encephalopathy associated with the use of metronidazole. Both patients showed characteristic abnormalities on magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) and recovered incompletely after the discontinuation of metronidazole. We also suggest that MRI with DWI may be useful in the diagnosis of metronidazole-induced encephalopathy, and that they have a role in the prediction of prognosis.