Souhel Najjar

Glia and epilepsy: excitability and inflammation

Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by non-neuronal cells, the glia--especially astrocytes and microglia--in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.

Neuroinflammation and psychiatric illness

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.

Neuroinflammation and white matter pathology in schizophrenia: systematic review

BACKGROUND Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear. METHOD We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia. RESULTS Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimers disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1β gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro-inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent. CONCLUSION Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis.

Epilepsy surgery in tuberous sclerosis: Multistage procedures with bilateral or multilobar foci

Refractory seizures are common in patients with tuberous sclerosis and can contribute to developmental delay and behavioral problems. Surgical intervention can reduce the seizure burden in selected patients with tuberous sclerosis and refractory epilepsy, thereby improving cognitive function, behavior, and quality of life. However, the risks of surgery are usually considered unacceptable when the epileptogenic focus lies over dominant hemisphere eloquent cortex or is multilobar. Multistage invasive monitoring can provide detailed data regarding the location and number of ictal foci and functional extraoperative mapping can precisely delineate the boundaries of eloquent areas of the brain. If independent ictal onsets are demonstrated, a staged surgical approach can allow a more aggressive yet safe procedure in selected patients. A combination of staged resection and multiple subpial transections may provide an opportunity to treat epileptogenic foci located over eloquent cortex. Bilateral staged resections can be used when independent bihemispheric foci are present in patients with tuberous sclerosis. This article presents two cases, one of which (case 2) was previously reported, on successful multistage surgical treatment of epileptogenic foci located over an eloquent cortex or in both hemispheres in children with tuberous sclerosis. This case is represented since there is additional follow-up available and the prior report was to a neurosurgical audience. This multistage approach permitted resection of epileptogenic foci that would traditionally have been considered inoperable. (J Child Neurol 2002;17:689-692).

Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder

BACKGROUND N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts, but these findings have not been systematically assessed in aggregate or in relation to methodological covariates. METHODS We searched MEDLINE, EMBASE, and PsycINFO for studies in any language that provided data on NMDAR antibody seropositivity or absolute serum titers in schizophrenia or schizoaffective, bipolar, or major depressive disorders. We used a random effects model to pool estimates across studies. RESULTS Nine studies met the eligibility criteria. Five studies (3387 participants) provided data on NMDAR antibody seropositivity in psychiatric versus control groups based on high-specificity seropositivity thresholds (cell-based assays [CBAs]: 1:320 dilution, 1:200 dilution, visual score>1; enzyme-linked immunosorbent assay [ELISA]: 90(th) percentile of control titers). Meta-analysis showed significantly higher odds of NMDAR antibody seropositivity among those with schizophrenia or schizoaffective, bipolar, or major depressive disorders compared with healthy controls (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.04-9.27; P=.043; I(2)=68%). Four studies (3194 participants) provided outcome data for these groups based on low-specificity seropositivity thresholds (CBAs 1:10 dilution; ELISA: 75(th) percentile of control titers). Meta-analysis showed greater heterogeneity and no significant between-group difference (OR, 2.31; 95% CI, 0.55-9.73; P=.25; I(2)=90%). Seropositive participants in psychiatric groups had various combinations of IgG, IgM, and IgA class antibodies against NR1, NR1/NR2B, and NR2A/NR2B subunits. Subgroup analysis revealed significantly higher odds of seropositivity among all participants based on 1:10 versus 1:320 dilution seropositivity thresholds (OR, 4.56; 95% CI, 2.41-8.62; P<.001; I(2)=0%; studies=2, n=2920), but no apparent difference between first-episode and chronic schizophrenia or schizoaffective disorder (OR, 1.15; 95% CI, 0.19-7.24; P=.88, I(2)=43%, studies=2, n=1108). Average NR2A/NR2B antibody titers determined by ELISA were significantly higher among participants with first-episode schizophrenia (P<.0001) and acute mania (P<.01) compared with healthy controls. Levels decreased by 58% at 8weeks in first-episode schizophrenia, and by about 13% at 4days in acute mania. CONCLUSIONS Individuals with schizophrenia or schizoaffective, bipolar, or major depressive disorders are collectively about three times more likely to have elevated NMDAR antibody titers compared with healthy controls based on high-specificity, but not low-specificity, seropositivity thresholds, though considerable methodological and statistical heterogeneity exists. Evidence concerning the effect of disease state and time of serum acquisition is varied and consistent, respectively. Adequately powered longitudinal studies employing standardized assay methods and seropositivity threshold definitions, and quantifying NMDAR antibodies in both sera and cerebrospinal fluid are needed to further elucidate the clinical and pathophysiological implications of this association.

Refractory epilepsy associated with microglial activation.

Background:Experimental and clinical studies support a pathogenic role of microglial activation and proliferation (MAP) in epileptogenesis. Methods:From a consecutive series of 319 surgically treated epilepsy cases, we retrospectively reviewed the histopathological sections of 92 cases to define the prevalence and severity of MAP after excluding the other 227 because of coexisting disorders that might contribute to MAP. Severity of MAP was compared with underlying abnormalities. We assessed the response to intravenous immunoglobulin and plasmapheresis in one patient with severe MAP who had failed multiple antiepileptic drugs and epilepsy surgery. Results:MAP was detected with routine (hematoxylin and eosin) stain in 46 of 92 cases (50%). MAP was mild in 32 cases (69.6%), moderate in 12 (26.1%), and severe in 2 (4.3%). The prevalence and severity of MAP were independent of underlying abnormalities. Immunomodulatory therapy was followed by a greater than 90% reduction in seizure activity in the treated patient. Conclusion:MAP is prevalent in resected human epilepsy tissue. Failure to down-regulate MAP contributes to chronic neuronal hyperexcitability. We hypothesize that MAP initiates a cycle of inflammation-induced seizures and seizure-induced inflammation. Microglia-driven epilepsy may be a primary pathogenic process in a small number of cases, as suggested by the pathology and therapeutic response in our patient, but may contribute to epileptogenesis in many more.

Bilateral resective epilepsy surgery in a child with tuberous sclerosis: case report.

OBJECTIVE AND IMPORTANCE Surgical intervention can reduce the burden of seizures in selected patients with tuberous sclerosis and medically refractory epilepsy. CLINICAL PRESENTATION A child presented with tuberous sclerosis and severe epilepsy beginning in the first month of life and delayed development before 1 year of age. Video-electroencephalographic monitoring at the age of 1 year revealed a left temporal seizure focus. Repeat video-electroencephalography at 2 years of age revealed a right posterior quadrant seizure focus. Bilateral subdural electrodes were placed, confirming independent seizure onsets from the right parietal area (overlying a tuber) and prominent interictal activity over the left superior temporal region. INTERVENTIONThe right parietal focus was resected, and electrodes were maintained over the left temporal focus. After right parietal resection, ictal discharges were recorded over the left temporal region; a corticectomy was performed 2 days later. No tonicoclonic or complex partial seizures have occurred during a follow-up period of more than 24 months. Simple partial motor seizures involving the right foot have been reduced by more than 80%, and other simple partial seizures have been eliminated. Postoperatively, there has been marked improvement in the patient’s cognitive and motor developmental status. CONCLUSIONIn selected patients with bilateral seizure foci involving separate lobes, aggressive bilateral surgery can be safe and effective.

Neuropsychiatric Autoimmune Encephalitis without Vgkc-complex, Nmdar, and Gad Autoantibodies: Case Report and Literature Review

We report a patient with a seronegative autoimmune panencephalitis, adding a subtype to the emerging spectrum of seronegative autoimmune encephalitis, and we review the sparse literature on isolated psychiatric presentations of autoimmune encephalitis. (A PubMed search for “seronegative autoimmune encephalitis,” “nonvasculitic autoimmune inflammatory meningoencephalitis,” and related terms revealed <25 cases.) A 15-year-old girl developed an acute-onset isolated psychosis with prominent negative symptoms and intermittent encephalopathy. Despite clinical worsening, her brain magnetic resonance imaging (MRI) scans remained normal for 7 years. Serology was negative for voltage-gated potassium channel (VGKC)-complex, N-methyl-D-aspartate receptor (NMDAR), and glutamic acid decarboxylase (GAD) autoantibodies. We excluded genetic, metabolic, paraneoplastic, degenerative, and infectious etiologies. The patient’s symptoms remitted fully with immune therapy, but recurred in association with widespread bihemispheric brain lesions. Brain biopsy revealed mild nonvasculitic inflammation and prominent vascular hyalinization. Immune therapy with plasma exchanges cleared the MRI abnormalities but, 10 years after onset, the patient still suffers neuropsychiatric sequelae. We conclude that autoimmune panencephalitis seronegative for VGKC-complex, NMDAR, and GAD autoantibodies is a subtype of autoimmune encephalitis that can present with pure neuropsychiatric features and a normal brain MRI. Immunologic mechanisms may account for psychiatric symptoms in a subset of patients now diagnosed with classical psychotic disorders. Delay in starting immune therapy can lead to permanent neuropsychiatric sequelae. We propose a standardized classification system for the autoimmune encephalitides, integrating earlier pathology-oriented terms with more recently defined serologic and clinical phenotypes.

Epilepsy Associated with Systemic Autoimmune Disorders

Systemic autoimmune disorders affect multiple organ systems. Brain involvement commonly causes seizures, which may be the presenting symptom. Systemic lupus erythematosus, Sjorgrens syndrome, Wegeners granulomatosis, sarcoidsosis, celiac disease, Crohns disease, Behcets, and Hashimotos encephalopathy are reviewed. Mechanisms underlying CNS pathology in systemic autoimmune disorders—and specifically factors predisposing these patients—are discussed, including vascular disease (e.g., prothrombotic state, anticardiolipin antibody, emboli, vasculitis), antineuronal antibodies, immune complexes, cytokines, metabolic disorders, infection, and therapy. Diagnostic and therapeutic strategies must be individualized for both the disorder and the patient. Systemic autoimmune disorders affect multiple organ systems and frequently involve the central and peripheral nervous systems. Seizures are among the most common neurological manifestation and occasionally can be the presenting symptom. There are many causes of seizures in systemic autoimmune disorders (Table 1), and the first clinical challenge is to determine not only the cause but also the significance of seizures. In some cases, they are clues to metabolic or infectious disorders or medication toxicity; in other cases, seizures herald a life-threatening progression of the underlying illness.

Anti-basal ganglia antibodies in primary obsessive-compulsive disorder: systematic review and meta-analysis

BACKGROUND Autoimmune-mediated basal ganglia dysfunction is implicated in the pathophysiology of neuropsychiatric disorders commonly manifesting with obsessive-compulsive features (e.g. Sydenham chorea). The relationship between autoimmunity and primary obsessive-compulsive disorder (OCD), however, is less clear. AIMS To pool data on serum and cerebrospinal fluid (CSF) anti-basal ganglia antibody (ABGA) positivity in primary OCD (without neurological or autoimmune comorbidity) relative to controls or neuropsychiatric disorders previously associated with increased odds of ABGA positivity. METHOD We performed electronic database and hand-searches for studies meeting pre-specified eligibility criteria from which we extracted data using a standardised form. We calculated pooled estimates of ABGA positivity using a random-effects model. RESULTS Seven case-control studies totalling 844 participants met the eligibility criteria. Meta-analysis showed that a significantly greater proportion of those with primary OCD were ABGA seropositive compared with various controls (odds ratio (OR) = 4.97, 95% CI 2.88-8.55, P<0.00001). This effect was not associated with heterogeneity or publication bias, and remained significant after stratifying the analysis by age, gender, disease severity, illness duration, immunostaining methodology, study quality, publication type, kind of control group, and sample size. There were no significant differences in ABGA seropositivity for comparisons between primary OCD and Tourette syndrome, attention-deficit hyperactivity disorder or paediatric acute-onset neuropsychiatric syndrome. RESULTS of one study testing CSF samples showed that a significantly greater proportion of participants with primary OCD were ABGA CSF-positive compared with healthy controls (OR = 5.60, 95% CI 1.04-30.20, P = 0.045). CONCLUSIONS Odds of ABGA seropositivity are increased fivefold in primary OCD compared with controls, but are comparable to those associated with disorders previously associated with ABGA, providing circumstantial evidence of autoimmunity in a subset of those with primary OCD. Further experimental studies are needed to ascertain whether this relationship is causal.