John DeToledo

Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways

Multiple sclerosis (MS) is a disease of the central nervous system that is characterized by the demyelination of neuronal axons. Four different patterns of demyelination have been described, showing the heterogeneity in the immunopathologic processes involved in the demyelination. This review will focus on reactive oxygen species (ROS)-related inflammation in MS. Special emphasis will be placed on the nuclear factor erythroid-2-related factor 2 (Nrf2) as it regulates the transcription of ROS-protective genes. In the cytosol, Nrf2 binds to Keap1 (Kelch-like ECH-associated protein 1), and together they are degraded by the 26S proteasome after ubiquitination. If challenged by ROS Nrf2, binding to Keap1 is abrogated, and it translocates into the nucleus. Here it binds to the antioxidant response element and to a small protein termed Maf (musculoaponeurotic fibrosarcoma oncogene homolog). This leads to an enhanced transcription of ROS protective genes and represents the physiological answer against ROS challenge. It has been shown that dimethyl fumarate (DMF) has the same effect and leads to an enhanced transcription of ROS-protective genes. This response is mediated through a reduced binding of Nrf2 to Keap1, thus resulting in a higher level of free Nrf2 in the cytosol. Consequently, more Nrf2 translocates to the nucleus, promoting transcription of its target genes. DMF has been used for the treatment of psoriasis for many years in Germany without the occurrence of major side effects. In psoriasis, DMF reduces ROS-related inflammation in skin. A DMF analog, BG-12, was recently approved for the treatment of relapsing-remitting MS by the European Union and the US Food and Drug Administration. As an oral formulation, it gives patients a convenient and effective alternative to the injectable immune modulators in the long-term treatment of MS.

Isolated left posterior insular infarction and convergent roles in verbal fluency, language, memory, and executive function.

The posterior insular cortex—a complex structure interconnecting various brain regions for different functions—is a rare location for ischemic stroke. We report a patient with isolated left posterior insular infarction who presented with multiple cognitive impairment, including impairment in semantic and phonemic verbal fluency.

Pupil to limbus ratio: Introducing a simple objective measure using two-box method for measuring early anisocoria and progress of pupillary change in the ICU

Introduction: Measurement of static pupillary size in the ICU is of importance in cases of acutely expanding intracranial mass lesions. The inaccuracies with subjective assessment of pupillary size by medical personnel preclude its use in emergent neurological situations. Objective: To determine if the ratio of pupil to limbus diameter (PLD ratio) measured by a two-box method is a reliable measure of pupil size for detecting early anisocoria and measuring pupillary changes. Materials and Methods: The PLD ratio was defined as the ratio of the pupillary diameter measured at a para-horizontal axial plane with the limbus diameter measured at the same or parallel axial plane. A two-box method was used to estimate the diameters of imaged pupils. Eyes were imaged using an iPhone 4S cellphone camera. Background illumination was measured and kept constant. The pupils of a 78-year-old woman, who presented with a large intra-axial parenchymal hemorrhage, were imaged. The patient had left pupillary miosis in dark but not in bright light. After presenting this case along with the images of the pupillary examination, a group of 21 medical staff were asked several questions on the pupillary examination. Reliability of PLD ratio were assessed via standard error of mean (S.E.M) of PLD ratios for 3 different subjects each imaged under constant illumination and fixation but from different angles to the optical axis. Results: Analysis of questionnaire data together with PLD ratios revealed that ~ 14% and 10% of participants could estimate the pupillary size in darkness and bright light respectively but none were simultaneously accurate indicating that subjective assessment of pupillary size was unreliable. The approach towards a systematic pupillary examination was inconsistent among the participants. The PLD ratio was found to be a reliable measure of pupillary size with standard error of mean below 0.1 mm for the three subjects tested. Conclusion: Static pupillary sizes can be objectively and consistently evaluated using PLD ratios using a two-box method. PLD ratios are resistant, within limits, to changes in imaging angle or choice of para-horizontal axes for measurement.

Topiramate-induced hyperammonemic encephalopathy in a patient with mental retardation: A case report and review of the literature

Hyperammonemia is an uncommon side effect of topiramate (TPM) that has only been reported when it is used as an adjunct to valproate. We report a patient with mental retardation who developed reversible encephalopathy from TPM. Ammonia level was monitored during the course of TPM treatment. This patient had recurring, reversible elevations in serum ammonia levels that coincided with the administration of TPM. To our knowledge, symptomatic hyperammonemia has not been reported to occur with TPM monotherapy.

Odorant Item Specific Olfactory Identification Deficit May Differentiate Alzheimer Disease From Aging

OBJECTIVES To explore whether the ability to recognize specific odorant items is differentially affected in aging versus Alzheimer disease (AD); to refine olfactory identification deficit (OID) as a biomarker of prodromal and early AD. DESIGN Prospective multicenter cross-sectional study with a longitudinal arm. SETTING Outpatient memory diagnostic clinics in New York and Texas. PARTICIPANTS Adults aged 65 and older with amnestic mild cognitive impairment (aMCI) and AD and healthy aging (HA) subjects in the comparison group. MEASUREMENTS Participants completed the University of Pennsylvania Smell Identification Test (UPSIT) and neuropsychological testing. AD-associated odorants (AD-10) were selected based on a model of ordinal logistic regression. Age-associated odorants (Age-10) were identified using a linear model. RESULTS For the 841 participants (234 HA, 192 aMCI, 415 AD), AD-10 was superior to Age-10 in separating HA and AD. AD-10 was associated with a more widespread cognitive deficit across multiple domains, in contrast to Age-10. The disease- and age-associated odorants clustered separately in age and AD. AD-10 predicted conversion from aMCI to AD. CONCLUSIONS Nonoverlapping UPSIT items were identified that were individually associated with age and disease. Despite a modest predictive value of the AD-specific items for conversion to AD, the AD-specific items may be useful in enriching samples to better identify those at risk for AD. Further studies are needed with monomolecular and unilateral stimulation and orthogonal biomarker validation to further refine disease- and age-associated signals.

Translational Correlation: Temporal Lobe Epilepsy and Hippocampal Sclerosis

Epileptic seizures are caused by abnormal brain electrical activities that originate primarily in the cortex. Even though the architecture of the neocortex seems to facilitate the initiation and propagation of these paroxysmal discharges, the phylogenetically older archicortex and paleocortex (hippocampus and parahippocampal gyrus) are a more common source or epileptic seizures in humans. The clinical manifestations of the seizure often reflect the area of the cortex in which the seizures originated. These seizures are commonly referred to as partial (focal) seizures. The first symptom of many partial seizures are the “aura” (simple partial seizure) that can then progress to alterations of awareness (complex partial seizures) and ultimately to a secondarily generalized tonic clonic seizure.

Risk of Seizure During Pregnancy

A 28-year-old woman presents to your office for consultation. She has been married for 2 years and is planning to start a family and become pregnant. She is diagnosed with partial epilepsy of temporal lobe origin 5 years ago and her seizures are controlled on lamotrigine 100 mg twice daily with no recurrence in the last year. She is worried about the risk of seizure medications to her baby should she become pregnant. She wants to stop taking lamotrigine during her pregnancy. How do you counsel her regarding the risk of seizure recurrence during pregnancy and potential seizure-related complications for her future pregnancy?