Peter A. Abdelmalik

Chronic in vitro ketosis is neuroprotective but not anti-convulsant.

J. Neurochem. (2010) 113, 826–835.

A Comparison of the Ability of a 4:1 Ketogenic Diet and a 6.3:1 Ketogenic Diet to Elevate Seizure Thresholds in Adult and Young Rats

Summary:  Purpose: The pentylenetetrazol (PTZ) infusion test was used to compare seizure thresholds in adult and young rats fed either a 4:1 ketogenic diet (KD) or a 6.3:1 KD. We hypothesized that both KDs would significantly elevate seizure thresholds and that the 4:1 KD would serve as a better model of the KD used clinically.

Increased seizure susceptibility of the hippocampus compared with the neocortex of the immature mouse brain in vitro.

Summary:  Purpose: The temporal lobe seems particularly susceptible to seizure activity. Mesial temporal lobe structures, including the hippocampus, have the lowest seizure thresholds in the brain. Conversely, thresholds in the frontal neocortex are significantly higher. The development of intact, isolated preparations of hippocampus and neocortex in vitro allows for study into mechanisms governing seizure threshold.

Magnesium as an effective adjunct therapy for drug resistant seizures.

OBJECTIVE To explore the use of magnesium (Mg), an endogenous ion and enzymatic co-factor used in a variety of medical applications, for the treatment of epileptic seizures resistant to traditional medical therapy. BACKGROUND For almost a century, Mg has been used as prophylaxis and treatment of seizures associated with eclampsia. Mg is a CNS depressant, with numerous functions intracellularly and extracellularly. However, because of the availability of well studied anticonvulsant drugs, Mg has not been tested widely in the treatment of epileptic seizures. METHODS A retrospective chart review of 22 cases of drug resistant epilepsy, where a trial of empiric oral Mg supplementation (mainly in the form of Mg-oxide) was conducted. RESULTS Oral Mg supplementation was associated with a significant decrease in the number of seizure days per month, from 15.3 ± 13.2 (mean ± SD) to 10.2 ± 12.6 at first follow up (3-6 months, p=0.021), and to 7.8 ± 10.0 seizure days/month at second follow up (6-12 months, p=0.004). Thirty-six percent had a response rate of 75% or greater at second follow-up. Two patients reported seizure freedom. Most patients were well maintained on MgO 420 mg twice a day, or in 2 cases, Mg Lactate, without significant adverse effects, the most frequent being diarrhea (4/22). DISCUSSION These results suggest that oral Mg supplementation may prove to be a worthwhile adjunctive medication in treating drug intractable epilepsy. CONCLUSIONS A prospective, double-blinded, placebo controlled study is warranted to evaluate the potential of Mg for the treatment of drug-resistant seizures.

Factors which abolish hypoglycemic seizures do not increase cerebral glycogen content in vitro

The brain is heavily dependant on glucose for its function and survival. Hypoglycemia can have severe, irreversible consequences, including seizures, coma and death. However, the in vivo content of brain glycogen, the storage form of glucose, is meager and is a function of both neuronal activity and glucose concentration. In the intact in vitro hippocampus isolated from mice aged postnatal days 8-13, we have recently characterized a novel model of hypoglycemic seizures, wherein seizures were abolished by various neuroprotective strategies. We had hypothesized that these strategies might act, in part, by increasing cerebral glycogen content. In the present experiments, it was found that neither decreasing temperature nor increasing glucose concentrations (above 2 mM) significantly increased hippocampal glycogen content. Preparations of isolated frontal neocortex in vitro do not produce hypoglycemic seizures yet it was found they contained significantly lower glycogen content as compared to the isolated intact hippocampus. Further, the application of either TTX, or a cocktail containing APV, CNQX and gabazine, to block synaptic activity, did not increase, but paradoxically decreased, hippocampal glycogen content in the isolated intact hippocampus. Significant decreases in glycogen were noted when neuronal activity was increased via incubation with l-aspartate (500 muM) or low Mg(2+). Lastly, we examined the incidence of hypoglycemic seizures in hippocampi isolated from mice aged 15-19 and 22-24 days, and compared it to the incidence of hypoglycemic seizures of hippocampi isolated from mice aged 8-13 days described previously (Abdelmalik et al., 2007 Neurobiol Dis 26(3):646-660). It was noted that hypoglycemic seizures were generated less frequently, and had less impact on synaptic transmission in hippocmpi from PD 22-24 as compared to hippocampi from mice PD 15-19 or PD 8-13. However, hippocampi from 8- to 13-day-old mice had significantly more glycogen than the other two age groups. The present data suggest that none of the interventions which abolish hypoglycemic seizures increases glycogen content, and that low glycogen content, per se, may not predispose to the generation of hypoglycemic seizures.

Anti-aging factor, serum alpha-Klotho, as a marker of acute physiological stress, and a predictor of ICU mortality, in patients with septic shock

Purpose: Genetic deletions decreasing serum alpha‐Klotho (alpha‐KL) have been associated with rapid aging, multi‐organ failure and increased mortality in experimental sepsis. We hypothesized that lower alpha‐KL obtained at the onset of septic shock correlates with higher mortality. Materials and methods: Prospective cohort of 104 adult patients with septic shock. Alpha‐KL was measured via ELISA on serum collected on the day of enrollment (within 72 h from the onset of shock). Relationship between alpha‐KL and clinical outcome measures was evaluated in uni‐ and multi‐variable models. Results: Median (IQR) alpha‐KL was 816 (1020.4) pg/mL and demonstrated a bimodal distribution with two distinct populations, Cohort A [n = 97, median alpha‐KL 789.3 (767.1)] and Cohort B [n = 7, median alpha‐KL 4365.1(1374.4), >1.5 IQR greater than Cohort A]. Within Cohort A, ICU non‐survivors had significantly higher serum alpha‐KL compared to survivors as well as significantly higher APACHE II and SOFA scores, rates of mechanical ventilation, and serum BUN, creatinine, calcium, phosphorus and lactate (all p ≤ 0.05). Serum alpha‐KL ≥ 1005, the highest tertile, was an independent predictor of ICU mortality when controlling for co‐variates (p = 0.028, 95% CI 1.143–11.136). Conclusions: Elevated serum alpha‐KL in patients with septic shock is independently associated with higher mortality. Further studies are needed to corroborate these findings.

Spontaneous Intraventricular Hemorrhage: When Should Intraventricular tPA Be Considered?

Abstract Spontaneous intracerebral hemorrhage (ICH) is the most common cause of intraventricular hemorrhage (IVH) in adults. Complicating approximately 40% of ICH cases, IVH adds to the morbidity and mortality of this often fatal form of stroke. It is also a severity factor that complicates subarachnoid hemorrhage and traumatic brain injury, along with other less common causes of intracranial bleeding. Medical and surgical interventions to date have focused on limiting ICH and IVH expansion, controlling intracranial pressure, and relieving obstructive hydrocephalus. The placement of an external ventricular drain (EVD) can achieve the latter two goals but has not demonstrated improvement in clinical outcomes beyond mortality reduction. More recently, intraventricular fibrinolysis, utilizing the EVD, has gained interest as a safe and potentially effective method to maintain catheter patency and facilitate hematoma removal. A recent phase III clinical trial evaluating the efficacy of intraventricular alteplase versus intraventricular saline showed a mortality benefit, but failed to meet the primary endpoint of significant functional improvement. However, planned subgroup analysis focusing on patients with IVH volume > 20 mL, and those with IVH removal > 85% suggest that significant functional benefits may be attainable with this therapy. The practice of intraventricular fibrinolysis for spontaneous IVH is not the standard of care; however, based on 20 years of experience, it meets thresholds as a safe intervention, and in those patients with a high burden of intraventricular blood, aggressive clearance may lead to improved quality of life in survivors of this morbid syndrome.

Nutritional and Bioenergetic Considerations in Critically Ill Patients with Acute Neurological Injury

The brain, due to intensive cellular processes and maintenance of electrochemical gradients, is heavily dependent on a constant supply of energy. Brain injury, and critical illness in general, induces a state of increased metabolism and catabolism, which has been proven to lead to poor outcomes. Of all the biochemical interventions undertaken in the ICU, providing nutritional support is perhaps one of the most undervalued, but potentially among the safest, and most effective interventions. Adequate provisions of calories and protein have been shown to improve patient outcomes, and guidelines for the nutritional support of the critically ill patient are reviewed. However, there are no such specific guidelines for the critically ill patient with neurological injury. Patients with primary or secondary neurological disorders are frequently undernourished, while data suggest this population would benefit from early and adequate nutritional support, although comprehensive clinical evidence is lacking. We review the joint recommendations from the Society for Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition, as they pertain to neurocritical care, and assess the recommendations for addressing nutrition in this patient population.

A Case of Acute Disseminated Encephalomyelitis in a Middle-Aged Adult.

Objectives. Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that is often preceded by infection or recent vaccination. Encephalopathy and focal neurological deficits are usually manifest several weeks after a prodromal illness with rapidly progressive neurologic decline. ADEM is most commonly seen in children and young adults, in which prognosis is favorable, but very few cases have been reported of older adults with ADEM and thus their clinical course is unknown. Methods. Here we present a case of ADEM in a middle-aged adult that recovered well after treatment. Results. A 62-year-old man presented with encephalopathy and rapid neurological decline following a gastrointestinal illness. A brain MRI revealed extensive supratentorial white matter hyperintensities consistent with ADEM and thus he was started on high dose intravenous methylprednisolone. He underwent a brain biopsy showing widespread white matter inflammation secondary to demyelination. At discharge, his neurological exam had significantly improved with continued steroid treatment and four months later, he was able to perform his ADLs. Conclusions. This case of ADEM in a middle-aged adult represents an excellent response to high dose steroid treatment with a remarkable neurological recovery. Thus it behooves one to treat suspected cases of ADEM in an adult patient aggressively, as outcome can be favorable.

Herpes Simplex Viral Encephalitis Masquerading as a Classic Left MCA Stroke

Objective. Stroke is a clinical diagnosis, with a history and physical examination significant for acute onset focal neurological symptoms and signs, often occurring in patients with known vascular risk factors and is frequently confirmed radiographically. Case Report. A 79-year-old right-handed woman, with a past medical history of hypertension, hyperlipidemia, and prior transient ischemic attack (TIA), presented with acute onset global aphasia and right hemiparesis, in the absence of fever or prodrome. This was initially diagnosed as a proximal left middle cerebral artery (MCA) stroke. However, CT perfusion failed to show evidence of reduced blood volume, and CT angiogram did not show evidence of a proximal vessel occlusion. Furthermore, MRI brain did not demonstrate any areas of restricted diffusion. EEG demonstrated left temporal periodic lateralized epileptiform discharges (PLEDs). The patient was empirically loaded with a bolus valproic acid and started on acyclovir, both intravenously. CSF examination demonstrated a pleocytosis and PCR confirmed the diagnosis of herpes simplex viral encephalitis (HSVE). Conclusions. HSVE classically presents in a nonspecific fashion with fever, headache, and altered mental status. However, acute focal neurological signs, mimicking stroke, are possible. A high degree of suspicion is required to institute appropriate therapy and decrease morbidity and mortality associated with HSVE.