First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient.

BACKGROUND: Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism. CASE PRESENTATION: Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well. CONCLUSIONS: One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus.

Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ-aminobutyric acid type A (GABAA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α-dihydroprogesterone, pregnanolone and allopregnanolone were, respectively, 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05) and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by aging in controls. We conclude that neurosteroidogenesis is defective in patients with SE.

Cerebrospinal fluid findings in non-infectious status epilepticus.

OBJECTIVE: Ictal activity itself can cause pathological cerebrospinal fluid (CSF) findings. However, data regarding pathological CSF findings caused by SE itself to date remain scarce. We here evaluated the frequency and specificity of pathological CSF findings in non-infectious SE. METHODS: We performed a retrospective analysis of CSF samples in adult patients with episodes of non-infectious SE, who had been admitted to the Department of Neurology, University Hospital of Cologne. The following parameters were assessed: cell count, protein, and lactate content, CSF/serum glucose quotient (QGlc), disturbances of blood-brain-barrier function assessed by CSF/serum albumin quotient (QAlb), and qualitative intrathecal IgG synthesis assessed by unmatched oligoclonal bands in CSF. RESULTS: We analysed 54 episodes of non-infectious SE in which CSF had been obtained. CSF pleocytosis was infrequent (6%). Elevated CSF protein content was present in 44% of all cases, whereas elevated CSF lactate content was found in 23% of the cases. A decreased QGlc was present in 9%. Dysfunction of blood-brain-barrier (BBBD) was the most frequent pathological finding, amounting to 55%. Unmatched oligoclonal bands in CSF were seen in 10% of non-infectious SE. Further analysis revealed that elevated CSF protein content was found predominantly in recfractory SE (p = 0.04). Elevated CSF lactate content was associated with shorter latency between onset of SE and CSF retrieval (p = 0.004), positive history of epilepsy (p = 0.02) and an acute symptomatic etiology (p = 0.04). BBBD was also present more often in acute symptomatic SE (p = 0.001) and was the sole pathological CSF parameter associated with clinical outcome: presence of BBBD was associated with a less favorable outcome (p = 0.02). SIGNIFICANCE: Non-infectious SE itself does not commonly cause CSF pleocytosis. Data suggest that the detection of CSF pleocytosis should prompt further diagnostics for an underlying infectious or neoplastic etiology. In contrast, elevation of CSF protein content and BBBD were found frequently in non-infectious SE.

EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis.

INTRODUCTION: The anti-NMDA receptor (NMDAr) encephalitis-associated syndrome includes neuropsychiatric symptoms, impaired consciousness, seizures, autonomic instability, and hypoventilation. The electroencephalographic (EEG) activity throughout the course of the disease has still not been well documented. We reviewed electroclinical data of patients with NMDAr encephalitis to characterize their EEG and its clinical correlation. MATERIAL AND METHODS: We retrospectively identified 16 patients with NMDAr encephalitis from 8 Spanish medical centers, 15 of whom underwent video-EEG in the acute phase. RESULTS: In 15 patients (11 females, median age: 37.4, range: 14-87 years), seizures occurred in 9 (60%) and status epilepticus (SE) in 5 (33.3%). Magnetic resonance imaging (MRI) was abnormal in 10 (66.6%), and CSF (cerebrospinal fluid) was normal in 3 and abnormal in 12, with positive PCR (polymerase chain reaction) for Mycoplasma pneumoniae (1/15) and herpes simple virus (1/15). An ovarian teratoma was found in 1 patient and other malignancies (small cell lung carcinoma) in 1 patient. The EEG was abnormal in the acute phase in 14/15 (93.3%). Extreme delta brush (EDB) was observed in 5 (33.3%), and the presence of EDB was associated with SE in all cases. Rhythmic delta activity without EDB was observed in 5 (33.3%), while excessive beta activity was present in 4 (26.6%). Extreme delta brush can follow a pattern of well-characterized electroclinical seizures. CONCLUSIONS: Almost invariably, patients with NMDAr encephalitis had abnormal EEG. The presence of EDB, which can follow a pattern of well-characterized electroclinical seizures, in our patients was associated with seizures and SE. These findings suggest that EDB could be an evolutive pattern of an SE in NMDAr encephalitis. This article is part of a Special Issue entitled "Status Epilepticus".

Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.

OBJECTIVE: To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies. METHODS: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported. RESULTS: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms. CONCLUSION: Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.

Do cytokines have any role in epilepsy?

OBJECTIVE: We analyzed cytokines levels in patients with epilepsy and new onset seizure and correlated it with various parameters. MATERIALS AND METHODS: After obtaining consent, serum samples from 100 patients with epilepsy or new onset seizure were prospectively collected in the immediate post-ictal phase. In 16 patients, a second sample was collected during the seizure-free period. The serum cytokine levels [TNF-alpha, IFN-gamma, IL-1beta, IL-2, IL-4, and IL-6] were assessed (ELISA) in these patients and 100 matched healthy controls. CSF analysis was carried out in 9 patients of this cohort, when clinically indicated. RESULTS: The type of seizures (n=100) was major (45), partial (41) and status epilepticus (SE=14), while the epilepsy syndromes were idiopathic generalized (53) and localization related (47). The detectable serum cytokines in the patient group (n=100) were: IL-6 (42), TNF-alpha (36), IL-2 (22), IL-4 (22), IFN-gamma (20) and IL-1 (11) compared to the controls. CSF IL-6 and IL-1 was detectable in 4/9 and 2/9 patients, respectively while, IL-2, IL-4, IFN-gamma was detectable 1 in each patient. Correlations were noted between male gender and IL-1beta (p=0.04), positive family history and IL-1beta (p=0.001), "no alcohol use" and TNF-alpha (p=0.05), more than one year history of epilepsy and IL-1beta (p=0.02), status epilepticus (SE) and IL-6 (p=0.04). There was no difference between the new onset seizures vs. epilepsy group. Serial analysis during the seizure-free period revealed a decrease in cytokine levels: TNF-alpha (25% to 12.5%), IFN-gamma (12.5% to 0%), IL-1 (25% to 0) and IL-2 (6.2% to 6.2%), IL-4 (18.8% to 0%) and IL-6 (18.8% to 6.2%). CONCLUSIONS: We found increased post-ictal serum cytokine levels in patients with several epilepsy syndromes.

EFA6A-like antibodies in paraneoplastic encephalitis associated with immature ovarian teratoma: a case report.

We describe a 19-year-old patient with paraneoplastic encephalitis associated with immature ovarian teratoma (OT), who presented with psychiatric symptoms, prolonged disturbance of consciousness, refractory status epilepticus, central hypoventilation, and various abnormal involuntary movements. Immunological characterization of the patient's serum and cerebrospinal fluid (CSF) demonstrated the presence of an autoantibody that colocalized with EFA6A, a brain-specific protein involved in the regulation of dendritic development of hippocampal neurons. Despite the severity of the symptoms, the patient showed significant neurological improvement following removal of the tumor and chemotherapy. This case suggests that physicians should rule out an OT in young women with encephalitis who present with the subacute-onset of psychiatric symptoms. Antibodies that colocalize with EFA6A are a valuable marker for early diagnosis of a potentially reversible paraneoplastic encephalitis associated with OT.

Biphasic clinical course and early white matter abnormalities may be indicators of neurological sequelae after status epilepticus in children.

Clinical course and serial neuroimaging findings are not fully described in children who have had neurological sequelae following status epilepticus. We found four patients who had neurological sequelae out of 42 children with status epilepticus in 2004. MRI studies were reviewed with specific attention to diffusion-weighted images (DWI) and the apparent diffusion coefficient (ADC). Proinflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6, were measured in the cerebrospinal fluid (CSF) (3 patients). The clinical course showed biphasic; initial status epilepticus and neurological exacerbation along with seizure recurrence four to five days after onset. Within three days after initial status epilepticus, CT (all patients) and MRI (2 patients) did not show any abnormalities. From four to ten days after onset, MRI demonstrated diffuse hyperintensity in the cerebral white matter on DWI and hypointensity on ADC maps in all patients. Diffuse brain atrophy progressed thereafter. Tumor necrosis factor-alpha or interleukin-6 was elevated in all patients. A biphasic clinical course may be a specific feature for neurological sequelae. The preferential white matter involvement on MRI and elevated CSF cytokines indicate that glial dysfunction may play an important role in the pathophysiology of status epilepticus-associated cerebral damage.

Cerebrospinal fluid nucleotide metabolites following non-convulsive status epilepticus.

The authors studied specific and sensitive indicators of neuronal adenosine triphosphate (ATP) depletion--hypoxanthine, xanthine and uridine levels--in the cerebrospinal fluid (CSF) of nine children during non-convulsive status epilepticus. No evidence of ATP depletion was found and CSF pH and creatine kinase levels were similar to those of controls. Hypoxanthine, xanthine and uridine had a tendency to be low, but this was significant only for xanthine. The authors speculatively link this reduction to a reduction in neuronal protein synthesis. This might be a mechanism whereby non-convulsive status epilepticus could lead to intellectual deterioration and dementia.

Postictal pleocytosis.

Six patients showed a transient and otherwise unexplained cerebrospinal fluid (CSF) pleocytosis following a flurry of generalized convulsions. Each had an obvious cause for repeated seizures. No evidence was found for an infectious, inflammatory, neoplastic, or other cause for the pleocytosis. All CSF specimens were clear and colorless, under normal pressure, and bacteriologically sterile. The maximal leukocyte count ranged from 9 to 80 per cubic millimeter and reached a maximum on the day after cessation of convulsions. No specimen contained more than 650 erythrocytes. Two patients initially had a mildly increased CSF protein; glucose values were unremarkable. We propose that the pleocytosis in these patients was a result of frequently repeated generalized convulsions. The mechanism of postictal pleocytosis is uncertain. It may result from transient breakdown of the blood-brain barrier, which has been demonstrated after seizures in experimental animals. Although infectious causes must first be considered and rigorously searched for, it appears that seizures alone may cause a transient CSF pleocytosis.