Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications

Insulin plays a key role in cognition and other aspects of normal brain function. Insulin resistance induces chronic peripheral insulin elevations, reduces insulin activity, and reduces brain insulin levels. The insulin resistance syndrome and associated conditions such as type 2 diabetes mellitus and hypertension, are associated with age-related memory impairment and Alzheimer disease. Our work has focused on potential mechanisms through which this association is forged, including the effects of peripheral hyperinsulinemia on memory, inflammation, and regulation of the beta-amyloid peptide. We have shown that raising plasma insulin to levels that characterize patients with insulin resistance invokes synchronous increases in levels of beta-amyloid and inflammatory agents. These convergent effects may impair memory and induce AD pathology. Therapeutic strategies focused on preventing or correcting insulin abnormalities may thus benefit adults with age-related memory impairment and AD.     

Common pathophysiologic mechanisms in migraine and epilepsy

Migraine and epilepsy are comorbid episodic disorders that have common pathophysiologic mechanisms. Migraine attacks, like epileptic seizures, may be triggered by excessive neocortical cellular excitability; in migraine, however, the hyperexcitability is believed to transition to cortical spreading depression rather than to the hypersynchronous activity that characterizes seizures. Some forms of epilepsy and migraine are known to be channelopathies. Mutations in the same genes can cause either migraine or epilepsy or, in some cases, both. Given the likely commonalities in the underlying cellular and molecular mechanisms, it is not surprising that some antiepileptic drugs, including valproate, topiramate, and gabapentin, are effective antimigraine agents. Ionotropic glutamate receptors play roles in both migraine and epilepsy, with NMDA receptors that are critical to cortical spreading depression of particular importance in migraine. Greater understanding of the shared mechanisms of epilepsy and migraine can provide a basis for the development of improved treatment approaches that may be applicable to both conditions.     

Acute spinal cord injury, part I: pathophysiologic mechanisms

Spinal cord injury (SCI) is a devastating and common neurologic disorder that has profound influences on modern society from physical, psychosocial, and socioeconomic perspectives. Accordingly, the present decade has been labeled the Decade of the Spine to emphasize the importance of SCI and other spinal disorders. Spinal cord injury may be divided into both primary and secondary mechanisms of injury. The primary injury, in large part, determines a given patient's neurologic grade on admission and thereby is the strongest prognostic indicator. However, secondary mechanisms of injury can exacerbate damage and limit restorative processes, and hence, contribute to overall morbidity and mortality. A burgeoning body of evidence has facilitated our understanding of these secondary mechanisms of injury that are amenable to pharmacological interventions, unlike the primary injury itself. Secondary mechanisms of injury encompass an array of perturbances and include neurogenic shock, vascular insults such as hemorrhage and ischemia-reperfusion, excitotoxicity, calcium-mediated secondary injury and fluid-electrolyte disturbances, immunologic injury, apoptosis, disturbances in mitochondrion function, and other miscellaneous processes. Comprehension of secondary mechanisms of injury serves as a basis for the development and application of targeted pharmacological strategies to confer neuroprotection and restoration while mitigating ongoing neural injury. The first article in this series will comprehensively review the pathophysiology of SCI while emphasizing those mechanisms for which pharmacologic therapy has been developed, and the second article reviews the pharmacologic interventions for SCI.     

The pathophysiologic mechanisms associated with hypotensive susceptibility

Introduction

Patients with vasovagal syncope (VVS) and positive tilt table test (TTT) were not found to benefit from pacing in the ISSUE-3 trial despite the presence of spontaneous asystole during monitoring. “Hypotensive susceptibility” unmasked by TTT was reported as a possible explanation. The purpose of this study was to assess the pathophysiologic mechanisms associated with hypotensive susceptibility.

Methods

366 consecutive patients with the diagnosis of VVS who also had TTT were identified. Baroreflex gain (BRG) in addition to blood pressure (BP) and heart rate (HR) responses during the first 20 min of TTT were analyzed and compared between patients with positive TTT (n = 275, 75 %) and negative TTT (n = 91, 25 %).

Results

The mean BRG was similar between the groups (12.5 ± 6.3 versus 12.4 ± 6.3 ms/mmHg, p = 0.72); however, an age-dependent decrease was noted (17.6 ± 4.8, 15.0 ± 6.0, 10.6 ± 4.2, 10.3 ± 6.4 and 9.9 ± 8.5 ms/mmHg for patients <21, 21–40, 41–60, 61–80 and >80 years old, respectively; p < 0.001). In addition, we saw a main effect of age on the type of response with a greater prevalence of a vasodepressor response in older subjects (p < 0.001). During the first 20 min of TTT, BP was similar in patients with tilt-positive VVS when compared with patients with tilt-negative VVS; however, HR was significantly lower.

Conclusion

BRG is similar in tilt-positive VVS patients when compared with tilt-negative VVS patients. An age-dependent decrease in BRG was noted with a higher prevalence of a vasodepressor response seen in older patients. The clinical significance of the blunted HR response in tilt-positive VVS remains to be determined.

     

Seizures and encephalitis: Clinical features, management, and potential pathophysiologic mechanisms

Encephalitis is an inflammation and swelling of the brain, which is often caused by a viral infection; it is an important cause of acute symptomatic seizures as well as subsequent epilepsy. Herein we describe the definition, epidemiology, and etiology of encephalitis as a cause of seizures. We then focus on encephalitis due to herpes simplex virus (the most common sporadic viral cause of encephalitis) and Japanese encephalitis virus (the most common epidemic viral cause). We also discuss the evidence for seizures occurring in the context of antibody-associated encephalitis, an increasingly important condition. Finally, we describe the acute and longer-term management of encephalitis-related seizures and their potential pathophysiologic mechanisms, concluding with the emerging etiologic role of human herpesvirus 6.     

Deep brain stimulation surgery for Parkinson's disease: mechanisms and consequences

Despite the introduction of new medications, motor fluctuations and dyskinesias disable a significant proportion of Parkinson's disease patients. This has lead to renewed interest in stereotactic neurosurgery. A skilled team is needed to ensure that patient assessment and selection, operative technique, intraoperative monitoring, and post-operative management are optimised. High frequency stimulation has similar effects to ablative surgery, and is generally preferred. The clinical effects and possible mechanisms of action of deep brain stimulation of the subthalamic nucleus and globus pallidus are reviewed.     

Photosensitive epilepsies and pathophysiologic mechanisms of the photoparoxysmal response.

OBJECTIVE: To identify the pathophysiologic mechanisms of the photoparoxysmal response (PPR) in various photosensitive epilepsy syndromes, and to discuss the relation between these pathophysiologic mechanisms and the classification of epilepsies and epileptic syndromes. BACKGROUND: The authors found two types of pathophysiologic mechanisms of PPRs (wavelength-dependent PPRs and quantity-of-light-dependent PPRs) in patients with idiopathic generalized epilepsy and hereditary dentatorubral-pallidoluysian atrophy. METHODS: Intermittent photic stimulation with wavelength-specific optical filters was performed in photosensitive epileptic patients: six patients had severe myoclonic epilepsy in infancy (SMEI), eight had localization-related epilepsy (LRE), and seven had symptomatic generalized epilepsy (SGE). RESULTS: Four of the six photosensitive SMEI patients had quantity-of-light-dependent PPRs. Five of the eight photosensitive LRE patients had wavelength-dependent PPRs. Four of the seven photosensitive SGE patients had wavelength-dependent PPRs, and two had quantity-of-light-dependent PPRs. CONCLUSIONS: The type of pathophysiologic mechanism for eliciting PPRs by low-luminance photic stimulation was closely related to the classification of the epilepsy syndrome.     

Optic nerve enlargement in Krabbe disease: a pathophysiologic and clinical perspective

Krabbe disease is an infantile-onset progressive leukodystrophy. The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy. The authors report a rare case of optic nerve enlargement early in infantile Krabbe disease. Their case demonstrates proximal prechiasmatic enlargement of the nerves. They discuss the pathophysiological and clinical correlation of optic nerve enlargement in Krabbe disease and in other disorders. Although Krabbe disease does not feature in initial differential of optic nerve enlargement in children, its inclusion and early identification facilitate a timely diagnosis of this rapidly progressive fatal disease.     

Semiology and nosology

While distinguishing three successive steps in the making of a diagnosis, the authors point out the premises of modern semiology. They refer to the work of K. Schneider (pragmatic approach), Jaspers, Bleuler and Janzarik (approach based on theoretical concepts), Kasanin and finally Langfeldt (empirical approach). Current approaches of semiology try to define diagnostic criteria. In that line of thinking, the school of Vienna, while establishing the insufficiency of all systems, proposes the adoption of a polydiagnostic approach that would eventually define consistent semiologies that refer with certainty to real nosological entities.     

An unusual variant of the dorsal midbrain syndrome in MS: clinical characteristics and pathophysiologic mechanisms

Patients with MS exhibit a broad diversity of ocular motor syndromes. We describe a patient with relapsing-remitting MS who developed an unusual variation of the dorsal midbrain syndrome, characterized by monocular convergent-retraction nystagmus in the right eye, accompanied by divergent-retraction nystagmus in the fellow eye upon attempted upward gaze. Examination also revealed a skew deviation with a left hyperdeviation and severe adduction limitation in the left eye during attempted right gaze. We propose that a left INO accounted for the inability of the left eye to adduct (and result in convergent-retraction) during attempted upward saccades. We consider the pathophysiologic mechanisms responsible for our observations and review important details of the dorsal midbrain ocular motor circuitry.     

Chronic daily headache: nosology and pathophysiology

Systematic scientific classification of primary headaches is inexact, relying on clinical features because the disorders lack diagnostic markers, although the International Headache Society classification has been successful in providing relatively homogenous clinical groups for pathophysiological and therapeutic studies. One area in which there have been particular difficulties and uncertainty is in classifying patients with frequent headache, particularly chronic daily headache. Clinical research on the topic is limited, and imprecise because of uncertainties of definition. Rigorous basic or applied clinical research is a rarity, attested to by a paucity of new publications in the past year. Accordingly, the scientific basis of chronic daily headaches remains to be determined. There is agreement on one issue: for headache specialists and neurologists this is an important clinical problem. We take the position that chronic daily headache is what it says--frequent headache. As hematologists make a diagnosis of anemia, which invites further investigation and sub-classification, neurologists might diagnose chronic daily headache not to imply that all its causes are the same but simply to begin the clinical process.     

Genetics and dementia nosology

In preparation for the development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed), the American Psychiatric Association convened workshops reviewing scientific evidence relevant to diagnosis of dementia. One of the domains covered was genetics, which is reviewed here. The following areas are reviewed: genetic data on Alzheimer's disease and other dementias; the impact of nosology on genetic research in terms of its potential to improve diagnostic sensitivity and specificity and to decrease heterogeneity; the impact of genetic research findings on nosology, specific diagnostic criteria, and subtypes; and recommendations and future directions. The focus is on Alzheimer's disease, where more genetic data are available, and other dementias are reviewed more briefly. In addition, a separate section reviews the relationship of genetic findings and mild cognitive impairment, a boundary zone between normal aging and dementia, particularly Alzheimer's disease.