Faculty Bibliography

Autoimmune encephalitis is a severe inflammatory disorder of the brain with diverse causes and a complex differential diagnosis. Recent advances in the past decade have led to the identification of new syndromes and biological markers of limbic encephalitis, the commonest presentation of autoimmune encephalitis. The successful use of serum and intrathecal antibodies to diagnose affected patients has resulted in few biopsy and postmortem examinations. In those available, there can be variable infiltrating inflammatory T cells with cytotoxic granules in close apposition to neurons, consistent with an inflammatory autoimmune basis, but true vasculitis is rarely seen. The exception is Hashimoto encephalopathy.

Granulomatous inflammation, the prototypical histopathology of adult and childhood vasculitis, is characterized by inflammation of blood vessels accompanied by giant cells and epithelioid cells in the walls of cerebral vessels ranging from small leptomeningeal veins to large named cerebral arteries. Headache, hemiparesis, mental changes, abnormal cerebrospinal fluid protein content, and pleocytosis are suggestive features that warrant brain and leptomeningeal biopsy to make the diagnosis certain and begin cytotoxic therapy to improve outcome.

Background and Aims: Contemplating the use of N-acetylcysteine as a neuroprotectant, with dextran as an antithrombotic for patients with NIHSS less than or equal to 5, we quantified treatment-relevant clinical characteristics of a sample of this patient population at a single stroke center over one year.
Method(s): Patients with NIHSSResult(s): One-hundred twenty-eight of 310 (41%) patients with ischemic stroke had NIHSSConclusion(s): Minor stroke symptoms may not be captured by the current NIHSS. This population rarely had renal or hepatic failure, making them good candidates for combination N-acetylcysteine and dextran

BACKGROUND AND PURPOSE/OBJECTIVE:-THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. EXPERIMENTAL APPROACH/METHODS:Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography-telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats, and treatment-naïve rat, mouse, chicken, dog and human tissue. KEY RESULTS/RESULTS:-THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than a species that did not (dog). CONCLUSION AND IMPLICATIONS/CONCLUSIONS:Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models.

BACKGROUND:Cognitive deficits (CDs) in schizophrenia affect poor outcome and real-world community functioning. Because redox imbalance has been implicated, among other factors, in the pathophysiology of CDs, antioxidant compounds may have a beneficial effect in their treatment. Red yeast rice (RYR), besides its lipid-lowering effect, exhibit antioxidant and anti-inflammatory. METHODS:Thirty-five schizophrenia outpatients (age range, 18-60 years) on stable antipsychotic treatment and assessed by neuropsychological (Wisconsin Card Sorting Test [WCST], Verbal Fluency, and Stroop task) and psychodiagnostic instruments (Brief Psychiatric Rating Scale) received RYR at daily dosage of 200 mg/d (total monacolin K/capsule content, 11.88 mg) for 12 weeks. RESULTS:Red yeast rice supplementation significantly improved WCST "perseverative errors" (P = 0.015), "total errors" (P = 0.017, P = 0.001), and phonemic fluency test (P = 0.008); a trend for improvement on other WCST variables ("nonperseverative errors," "perseverative responses," and "categories") was observed. Effect sizes, according to Cohen's suggestions, were small in all explored cognitive dimensions. There were no significant change in clinical symptoms and no subject-reported adverse effects. CONCLUSIONS:Despite several limitations (open design, lack of a control group, short period of observation, small sample size, mode of controlling patients' compliance, the lack of assessment of patients' functional improvement), results suggest that RYR supplementation may be a potentially promising strategy for addressing CDs in schizophrenia; further randomized, placebo-controlled studies are needed to better evaluate the potential role of RYR for the treatment of CDs in schizophrenia.

Background: Research based Developmental Theory of Somatoform/Centralized Pain (S/CP) (Landa et al., 2012) suggests that early interpersonal adversity(EIA) interacts with multigenerational factors leading to neural predisposition to S/CP. Interpersonal affect regulation between infant and caregiver is crucial for optimal maturation of nervous system; EIA may impede development of capacities for emotion-somatic sensation differentiation, awareness, expression and regulation of emotions, leading to experiencing distress in somaticaly. These mechanisms of symptom formation suggest that psychotherapies targeting development of these capacities can help treat S/CP; studies show that psychotherapies that focus on emotion expression and working through interpersonal traumas can alleviate S/CP. However, the exact neurophysiologic mechanisms underlying these effects are not yet fully understood. In our previous study, 90% of S/CP patients (vs 10% of controls) presented with the Unmet Need for Closeness with Others (UNCO) as main representation of relationships. We now present the data on autonomic regulation (HRV) and verbally expressed emotions/alexithymia during patient's interviews on interpersonal relationships.
Method(s): Twenty patients with S/CP from Pain, Neurology, and Primary Care clinics, and 20 age-, sex-, ethnicity-, and level of education-matched healthy controls completed the Relationship Anecdotes Paradigm (RAP)-a semi-structured interview coded for representations of relationships (Core Conflictual Relationship Theme method). HRV was measured continuously during RAP. RAP narratives were coded for Verbally Expressed Emotion using coding method adapted from Levels of Emotional Awareness Scale.
Result(s): S/CP patients had higher levels of UNCO and RAP alexithymia, and significant increase in HRV during RAP vs controls. Relationship between these dimensions and history of interpersonal traumas will be explored.
Discussion(s): Talking about interpersonal relationships and expressing UNCO to others was associated with HRV increase among S/CP patients, which has direct implications for psychophysiologic mechanisms underlying change in psychotherapeutic interventions for S/CP, therefore helping reverse effects of EIA suggested by the Developmental Theory of S/CP. Implications for diagnosis and treatment of S/CP will be discussed

Depression affects a large proportion of patients with epilepsy, and is likely due in part to biological mechanism. Hormonal dysregulation due to the disruptive effects of seizures and interictal epileptiform discharges on the hypothalamic-pituitary-adrenal axis likely contributes to high rates of depression in epilepsy. This paper reviews the largely unexplored role of neuroendocrine factors in epilepsy-related depression, focusing on Growth Hormone (GH). While GH deficiency is traditionally considered a childhood disorder manifested by impaired skeletal growth, GH deficiency in adulthood is now recognized as a serious disorder characterized by impairments in multiple domains including mood and quality of life. Could high rates of depression in patients with epilepsy relate to subtle GH deficiency? Because GH replacement therapy has been shown to improve mood and quality of life in patients with GH deficiency, this emerging area may hold promise for patients suffering from epilepsy-related depression.

Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.

The diagnosis of primary central and peripheral nerve vasculitides should be established with certainty if suspected before commencing potent immunosuppressive therapy. The aim of induction therapy is to rapidly control the underlying inflammatory response and stabilize the blood-brain and blood-nerve barriers, followed by maintenance immunosuppression tailored to the likeliest humoral and cell-mediated autoimmune inflammatory vasculitic processes.