White matter integrity after cannabidiol administration for treatment resistant epilepsy.

OBJECTIVE: The effects of individual cannabinoids on white matter integrity are unclear. Human studies have shown white matter maturation alterations in regular recreational cannabis users with the magnitude of these effects dependent on the age of exposure. However, studies have yet to determine which phytocannabinoids are most responsible for these changes. In the current study, we analyzed the effects of pharmaceutical grade cannabidiol oral solution (CBD; Epidiolex® in the U.S.; Epidyolex® in the EU; 100 mg/mL oral solution) on white matter integrity using diffusion MRI in patients with treatment resistant epilepsy (TRE). METHODS: 15 patients with TRE underwent 3 T diffusion MRI prior to receiving CBD and then again approximately 12 weeks later while on a stable dose of CBD for at least two weeks. DTI analyzes were conducted using DSI Studio and tract-based spatial statistics (TBSS). RESULTS: DTI analysis using DSI Studio showed significant increases in fractional anisotropy (FA) in the right medial lemniscus (p = 0.03), right superior cerebellar peduncle (p = 0.03) and the pontine crossing tract (p = 0.04); decreased mean diffusivity (MD) in the left uncinate fasciculus (p = 0.02) and the middle cerebellar peduncle (p = 0.04); decreased axial diffusivity (AD) in the left superior cerebellar peduncle (p = 0.05), right anterior limb of the internal capsule (p = 0.03), and right posterior limb of the internal capsule (p = 0.02); and decreased radial diffusivity (RD) in the middle cerebellar peduncle (p = 0.03) and left uncinate fasiculus (p = 0.01). The follow-up ANCOVA also yielded significant results when controlling for covariates of CBD dosage, age, sex, change in seizure frequency, and scanner type: FA increased in the pontine crossing tract (p = 0.03); RD decreased in the middle cerebellar peduncle (p = 0.04) and left uncinate fasciculus (p = 0.04). Subsequent TBSS analysis controlling for the same variables yielded no significant white matter differences between groups. CONCLUSION: These findings indicate relatively minor short-term effects of highly-purified plant-derived CBD on white matter structural integrity in patients with TRE.

The effect of medial temporal lobe epilepsy on visual memory encoding.

Effective visual memory encoding, a function important for everyday functioning, relies on episodic and semantic memory processes. In patients with medial temporal lobe epilepsy (MTLE), memory deficits are common as the structures typically involved in seizure generation are also involved in acquisition, maintenance, and retrieval of episodic memories. In this study, we used group independent component analysis (GICA) combined with Granger causality analysis to investigate the neuronal networks involved in visual memory encoding during a complex fMRI scene-encoding task in patients with left MTLE (LMTLE; N=28) and in patients with right MTLE (RMTLE; N=18). Additionally, we built models of memory encoding in LMTLE and RMTLE and compared them with a model of healthy memory encoding (Nenert et al., 2014). For those with LMTLE, we identified and retained for further analyses and model generation 7 ICA task-related components that were attributed to four different networks: the frontal and posterior components of the DMN, visual network, auditory-insular network, and an "other" network. For those with RMTLE, ICA produced 9 task-related components that were attributed to the somatosensory and cerebellar networks in addition to the same networks as in patients with LMTLE. Granger causality analysis revealed group differences in causality relations within the visual memory network and MTLE-related deviations from normal network function. Our results demonstrate differences in the networks for visual memory encoding between those with LMTLE and those with RMTLE. Consistent with previous studies, the organization of memory encoding is dependent on laterality of seizure focus and may be mediated by functional reorganization in chronic epilepsy. These differences may underlie the observed differences in memory abilities between patients with LMTLE and patients with RMTLE and highlight the modulating effects of epilepsy on the network for memory encoding.

Age at stroke determines post-stroke language lateralization.

PURPOSE: To determine how age at the time of left middle cerebral artery stroke affects language lateralization in a combined sample of subjects with perinatal, childhood, and adult stroke. METHODS: 19 participants who had perinatal stroke (<1 month of age), 32 with later stroke, and 51 sex-/age-matched healthy controls (HCs) received fMRI of language using verb generation task (VGT). RESULTS: Percent lesion volumes were not different between groups (perinatal vs. late stroke) when taking brain volume into account (p = 0.084). Perinatal stroke group showed bilateral signal increases compared to more left-lateralized signals in matched HCs; late stroke group and HCs both showed left-hemispheric signal increases. LIs in the stroke groups were consistently more bilateral than in HCs (all p < 0.008) except for the late group's posterior LI (p = 0.080). There was greater proportion of leftward language lateralization in HCs compared to their respective stroke groups (78.9% vs. 31.6% in perinatal; 87.5% vs. 59.4% in late stroke; p = 0.004) and a larger proportion of leftward lateralization in late compared to perinatal stroke (p = 0.039). The age of stroke occurrence showed significant positive associations with global and frontal LI (both p ≤ 0.007). CONCLUSION: As expected, the age of stroke occurrence affects subsequent verb generation lateralization. Greater cortical plasticity is observed in earlier stroke while later stroke is associated with reliance on the repair of the previously damaged left-hemispheric networks.

Clinical outcomes following prolonged refractory status epilepticus (PRSE).

BACKGROUND: To define the clinical profile and outcome of patients in prolonged refractory status epilepticus (PRSE), and investigate possible predictors of outcome. METHODS: We reviewed 63 consecutive patients with PRSE cared for in the medical and neurointensive care units of three academic medical centers over a 9-year period. For this multi-center retrospective cohort study, PRSE was defined as SE that persisted despite at least 1 week of induced coma. Variables examined for their relationship to outcome included etiology, EEG, neuroimaging, and age. RESULTS: Forty-two (66%) of 63 patients in PRSE survived to discharge from hospitalization. Fourteen (22%) patients had a good outcome (mRS ≤ 3) at last available follow up (at least 6 months post-PRSE). Of these, 6 (10%) individuals had no significant disability and were able to carry out all usual activities (mRS = 1). Normal neuroimaging and a reactive EEG at onset of PRSE were associated with good outcome. Good or excellent clinical outcomes were possible in patients in PRSE for up to 79 days, and in patients up to 69 years old. CONCLUSIONS: Good outcome is not unusual in PRSE, including in some older patients, in a variety of diagnoses, and despite months of coma.

The US health care system: Part 1: Our current system.

The US health care crisis is of great concern to American neurologists. The United States has the world's most expensive health care system yet one-sixth of Americans are uninsured. The cost and volume of procedures is expanding, while reimbursement for office visits is declining. Pharmaceutical costs, durable goods, and home health care are growing disproportionately to other services. Carriers spend more for their own administration and profit than on payments to physicians. This first article on the US health care system identifies problems and proposes solutions, many of which are championed by the American Academy of Neurology through its legislative and regulatory committees.

Invited article: the US health care system: part 2: proposals for improvement and comparison to other systems.

In the search for a universal, high quality, affordable health care system, Americans seek to identify and correct a series of current problems. In part one of this two-part series, we presented problems along with some suggested actions. This second part presents other health care systems in Europe and Canada. These different systems provide universal care and at a lower cost than in the United States. Further domestic proposals are presented from the Massachusetts plan and positions from US presidential candidates. These systems and proposals raise ideas about possible changes in the US health care system. Knowledge of these issues and other health care systems will help foster a meaningful dialog about changes in the US health care system.

Functional magnetic resonance imaging reveals atypical language organization in children following perinatal left middle cerebral artery stroke.

We used verb generation and story listening tasks during fMRI to study language organization in children (7, 9 and 12 years old) with perinatal left MCA infarctions. Healthy, age-matched comparison children (n = 39) showed activation in left Broca's area during the verb generation task; in contrast, stroke subjects showed activation either bilaterally or in the right hemisphere homologue during both tasks. In Wernicke's area, comparison subjects showed left lateralization (verb generation) and bilateral activation (L > R) (story listening). Stroke subjects instead showed bilateral or right lateralization (verb generation) and bilateral activation (R > L) (story listening). Language is distributed atypically in children with perinatal left hemisphere stroke.

Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study.

OBJECTIVE: Valproic acid (VPA) is a commonly used anticonvulsant with multiple systemic effects. The purpose of this pilot study is to examine the blood genomic expression pattern associated with VPA therapy in general and secondly VPA efficacy in children with epilepsy. MATERIALS AND METHODS: Using oligonucleotide microarrays, gene expression in whole blood was assessed in pediatric epilepsy patients following treatment with VPA compared with children with epilepsy prior to initiation of anticonvulsant therapy (drug free patients). RESULTS: The expression of 461 genes was altered in VPA patients (n = 11) compared with drug free patients (n = 7), among which a significant number of serine threonine kinases were down-regulated. Expression patterns in children seizure free on VPA therapy (n = 8) demonstrated 434 up-regulated genes, many in mitochondria, compared with VPA children with continuing seizures (n = 3) and drug free seizure patients (n = 7). CONCLUSION: VPA therapy is associated with two significant and unique blood gene expression patterns: chronic VPA monotherapy in general and a separate blood genomic profile correlated with seizure freedom. These expression patterns provide new insight into previously undetected mechanisms of VPA anticonvulsant activity.

Language lateralization in left-handed and ambidextrous people: fMRI data.

BACKGROUND: It is generally accepted that most people have left-hemispheric language dominance, though the actual incidence of atypical language distribution in non-right-handed subjects has not been extensively studied. The authors examined language distribution in these subjects and evaluated the relationships between personal handedness, family history of sinistrality, and a language laterality index (LI) measured with fMRI. METHODS: The authors used whole-brain fMRI to examine 50 healthy, non-right-handed subjects (Edinburgh Handedness Inventory quotient between -100 and 52) while they performed language activation and nonlinguistic control tasks. Counts of active voxels (p < 0.001) were computed in 22 regions of interest (ROI) covering both hemispheres and the cerebellum. LI were calculated for each ROI and each entire hemisphere using the formula [L - R]/[L + R]. RESULTS: Activation was predominantly right hemispheric in 8% (4/50), symmetric in 14% (7/50), and predominantly left hemispheric in 78% (39/50) of the subjects. Lateralization patterns were similar for all hemispheric ROI. Associations were observed between personal handedness and LI (r = 0.28, p = 0.046), family history of sinistrality and LI (p = 0.031), and age and LI (r = -0.49, p < 0.001). CONCLUSIONS: The incidence of atypical language lateralization in normal left-handed and ambidextrous subjects is higher than in normal right-handed subjects (22% vs 4-6%). These whole-brain results confirm previous findings in a left-handed cohort studied with fMRI of the lateral frontal lobe. Associations observed between personal handedness and LI and family history of handedness and LI may indicate a common genetic factor underlying the inheritance of handedness and language lateralization.

Four-year incidence of psychogenic nonepileptic seizures in adults in hamilton county, OH.

In this retrospective study, the incidence of psychogenic nonepileptic seizures in Hamilton County, OH, between 1995 and 1998 was determined. The mean incidence of psychogenic nonepileptic seizures was 3.03/100,000, with the highest incidence in 1998 (4.6/100,000). Most patients with the diagnosis of psychogenic nonepileptic seizures were aged 25 to 45 years (4.38/100,000).

Neutrophils and reactive oxygen intermediates mediate glucan-induced pulmonary granuloma formation through the local induction of monocyte chemoattractant protein-1.

Monocyte chemoattractant protein-1 (MCP-1), which is required for full development of glucan-induced granulomas, in the rat, is expressed in the walls of blood vessels at sites of glucan embolization. Early (1 hour) vessel wall expression of MCP-1 is temporally and anatomically linked to the transient accumulation of neutrophils, even though these cells are not present within definitive lesions. To ascertain the potential pathophysiologic role of neutrophils in glucan-induced granuloma formation, rats were neutrophil-depleted using specific antiserum. There was a marked reduction in mean granuloma size and number in neutrophil-depleted animals when compared with neutrophil-sufficient controls. To determine potential mechanisms through which neutrophils may participate in granuloma formation, the antioxidant enzymes superoxide dismutase and catalase were administered to neutrophil-sufficient animals that had received glucan. Superoxide dismutase treatment did not reduce granuloma formation, whereas catalase treatment resulted in decreased granuloma size, suggesting that H2O2 plays an important role in this process. The local expression of MCP-1 mRNA and protein, as determined by in situ hybridization and immunohistochemical analysis, respectively, was decreased in both neutrophil-depleted and catalase-treated animals but not in superoxide dismutase-treated rats. Quiescent human umbilical vein endothelial cells incubated with either H2O2 or activated neutrophils secreted MCP-1. These data indicate that neutrophils and H2O2 are required for both full granuloma development and early blood vessel wall-associated MCP-1 expression after glucan infusion. These in vivo data, coupled with in vitro data that indicate that both catalase-sensitive reagent H2O2 and neutrophil-derived reactive oxygen intermediates (ie, H2O2) can induce MCP-1 secretion by human umbilical vein endothelial cells, support the hypothesis that neutrophils and neutrophil-derived products (H2O2) influence granuloma formation through induction of local MCP-1 expression.