Stephen L. Jaffe

Central pontine myelinolysis, an update

Abstract Central pontine myelinolysis (CPM) can be regarded as one of the demyelinating syndromes. First described by Adams et al. in 1959 in their chronic alcoholic patients, it has now been described in the malnourished, the chronically debilitated, the renal, the hepatic and the transplant patient among others. Pathologically, it is defined as a symmetric area of myelin disruption in the center of the basis pontis, although similar symmetric lesions have also been described occurring with CPM as well as independently in other brain areas (extrapontine myelinolysis or EPM) including the cerebellar and neocortical white/gray junctional areas, thalamus and striatum. Possible mechanisms include a hyperosmotically induced demyelination process resulting from rapid intracellular/ extracellular to intravascular water shifts producing relative glial dehydration and myelin degradation and/or oligodendroglial apoptosis. The process most often occurs during rapid rebalancing of the electrolyte parameters in the hyponatremic patient. Avoidance of CPM/EPM is dependent upon recognizing those patients with conditions pre-disposing them to osmotic myelinolysis and then moderating the rate of normalization of the electrolyte imbalance. The morbidity and mortality of CPM/EPM has been greatly reduced by recognition of pre-disposing conditions, increased understanding of the pathophysiology, intensive treatment, and rapid diagnosis and monitoring with advanced neuroimaging.

Cerebrospinal Fluid Analysis in Multiple Sclerosis

Although the diagnosis of multiple sclerosis (MS) may be clinically suspect and the magnetic resonance imaging findings compatible, cerebrospinal fluid (CSF) analysis remains mandatory in order to support the diagnosis. This is especially important since our understanding of the defining disease pathogenesis remains incomplete. However, there is no specifically diagnostic CSF test. And until recently, laboratory techniques for CSF analysis had not been rigorously standardized. Unconcentrated CSF without fixative should be used for the determinations of cell count and differential, protein and glucose, lactate, myelin basic protein, and the CSF/serum albumin ratio which is an indicator of blood-CSF barrier disruption. Additionally, CSF immunoglobulin-gamma (IgG) determinations are of major importance and are now included in the MS diagnostic criteria. Testing for oligoclonal IgG bands utilizing isoelectric focusing with IgG immunoblotting, the IgG synthesis rate, and the IgG index should be included. CSF analysis for kappa light chains and IGM may be diagnostically helpful. The search for biomarkers including those possibly present in the CSF which could predict and assess the course as well as response to treatment in a particular MS patient has not yet been successful. CSF immunoglobulin and T-cell/B-cell patterns, soluble HLA class I and II antigens, nitrous oxide metabolites, neurofilament and microtubule components and antibodies, tau protein, 14-3-3-protein, neuronal cell and intercellular adhesion molecules, and chemokines are actively being investigated as MS biomarkers.

Chapter 8 The Molecular and Cellular Pathogenesis of Dementia of the Alzheimer's Type: An Overview

The pathogenesis of dementia of the Alzheimers type (DAT) remains elusive. The neurodegeneration occurring in this disease has been traditionally believed to be the result of toxicity caused by the accumulation of insoluble amyloid-beta 42 (AB) aggregates, however recent research questions this thesis and has suggested other more convincing cellular and molecular mechanisms. Dysfunction of amyloid precursor protein metabolism, AB generation/aggregation and/or degredation/clearance, tau metabolism, protein trafficking, signal transduction, heavy metal homeostasis, acetylcholine and cholesterol metabolism, have all been implicated etiologically especially as to production of neurotoxic by-products occurring as a result of a specific process derangement. In this paper, these and other research directions are discussed as well as their implications for future therapies. The relationship of the proposed abnormal molecular and cellular processes to underlying genetic mutations is also scrutinized, all in an attempt to stimulate further insight into the pathogenesis of, and thus therapeutics for this increasingly prevalent disease.

Neurologic presentations of systemic vasculitides.

Vasculitis or angiitis refers to a group of inflammatory disorders of the blood vessels that cause structural damage to the affected vessel, including thickening and weakening of the vessel wall, narrowing of its lumen, and, usually, vascular necrosis. Systemic vasculitis is classified according to the vessel size and histopathologic and clinical features. Vasculitides with small vessel involvement typically include Henoch-Schönlein purpura and cryoglobulinemia. Polyarteritis nodosa and Wegener granulomatosis are small- and medium-sized vessel vasculitides, whereas temporal arteritis and Takayasu arteritis involve large vessels. In this article, the authors provide a review of the neurologic presentations of the major systemic vasculitides.

Early onset dementia.

Dementia is characterized by a decline in cognitive faculties and occurrence of behavioral abnormalities which interfere with an individuals activities of daily living. Dementing disorders usually affect elderly individuals but may occur in individuals younger than 65 years (early-onset dementia or EOD). EOD is often misdiagnosed or its diagnosis is delayed due to the fact that it has a more varied differential diagnosis than late-onset dementia. EOD affects individuals at the height of their career and productivity and produces devastating consequences and financial loss for the patients family as well as society. EOD is not uncommon and is diagnosed in up to a third of patients presenting with dementia. Most importantly, some of the causes of EOD are curable which makes the need for a specific and timely diagnosis crucial. The present chapter presents a systematic approach to the differential diagnosis of EOD and provides readers with the clinical and neuroimaging features of these disorders as well as important considerations for their diagnostic evaluation. Specifically, the nuances of assessing the history and examination are discussed with careful attention to the various methods of cognitive and behavioral evaluation. A step-wise approach to diagnostic testing is followed by a discussion of anatomical localization, which often aids in identifying specific etiologies. Finally, in order to organize the subject for the reader, the various etiologies are grouped under the general categories of vascular, infectious, toxic-metabolic, immune-mediated, neoplastic/metastatic, and neurodegenerative.

Cavernous angioma: a clinical study of 35 cases with review of the literature.

Abstract Background: Cavernous angioma is a vascular malformation which can be found in any region within the central nervous system. Objectives: There are few clinical and demographic cavernous angioma studies with large sample sizes. Therefore, the present study was designed to provide further information on the clinical and demographic characteristics of cavernous angioma using a relatively large sample of Persian patients. Methods: Patients with cavernous angioma were recruited from the outpatient neurology clinics in Isfahan, Iran, from October 2003 to October 2006. Results: In all cases, the diagnosis of cavernous angioma was based on brain magnetic resonance imaging. There were 35 patients (female/male: 17 : 18) identified with cavernous angioma. The mean age at presentation was 28.8 years. Initial manifestations included seizures in 16, headache in 11 and intracranial hemorrhage in eight patients. During follow-up, all patients experienced seizures and 19 developed headaches. Depression, vertigo, nausea, vomiting, disequilibrium, loss of consciousness and sensorimotor symptoms were also observed. Conclusion: Some of the findings of the present study were in accordance with previous studies. However, more of our patients with positive family history had solitary rather than multiple lesions, and more of our patients had generalized tonic–clonic seizures rather than partial seizures. Moreover, our data demonstrated that if there is a history of cavernous angioma with intracranial hemorrhage in family members, the presenting cavernous angioma patient is more prone to intracranial hemorrhage.

Cryptococcal meningitis presenting as pseudosubarachnoid hemorrhage.

A 50-year-old man presented with progressive visual loss, headache, and two days of confusion. A computed tomography of his head suggested subarachnoid hemorrhage with accompanying right parietal ischemic infarction. The magnetic resonance image was consistent with right parietal perisulcal pial and superficial cortical inflammation; a subjacent vasogenic edema with a 1 cm diameter abscess was also present. Funduscopy revealed bilateral multifocal choroidal lesions and retinal perivascular sheathing. He was diagnosed with pseudosubarachnoid hemorrhage secondary to cryptococcal meningitis and choroidal microabscesses with retinal inflammation after a cerebrospinal fluid (CSF) examination revealed cryptococcal yeast forms, as well as high titers of CSF cryptococcal antigen, but no CSF red blood cells.

Neurologic Presentations of Hepatic Disease

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in the context of portosystemic venous shunting, in the presence or absence of intrinsic hepatic disease. HE is clinically characterized by altered sensorium and a spectrum of neuropsychiatric abnormalities. Several hypotheses have been proposed to explain the underlying pathogenic mechanisms of altered brain function associated with advanced hepatic disease and portosystemic shunting. HE may lead to profound coma and death; however, in many cases it is reversible. This article discusses the most recent developments in understanding the pathophysiology of HE and its diagnosis and management.

Soluble HLA Class I and Class II Molecules in Relapsing-Remitting Multiple Sclerosis: Acute Response to Interferon-β1a Treatment and Their Use as Markers of Disease Activity

Abstract: During relapses in relapsing‐remitting multiple sclerosis (RRMS), serum soluble HLA class I surface antigen (sHLA‐I) levels are reported to either decrease or remain unchanged, whereas serum sHLA‐II levels increase. Interferon‐β1b therapy was recently reported to increase serum sHLA‐I in RRMS. In the present prospective study, solid‐phase enzyme‐linked immunosorbent assay was used to measure sHLA‐I and sHLA‐II in the sera of 21 RRMS patients during a clinical exacerbation, and then six weeks after treatment with high‐dose interferon‐β1a (IFN‐β1a). Pretreatment serum sHLA‐I was significantly lower in patients than in normal controls (P < 0.0005). Pretreatment sHLA‐II was also significantly lower than in normal controls (P= .003) unless enhancing MRI lesions (objectified relapse) were present; then sHLA‐II levels were similar to normal controls (relative increase). Six weeks after initiation of IFN‐β1a treatment, a significant increase in serum sHLA‐I was observed in all 21 RRMS patients (P < .0005). Conversely, serum sHLA‐II decreased significantly after treatment in the entire patient group (P < .0005). The acute effect of IFN‐β1a on serum sHLA‐I and sHLA‐II was observed to be the opposite of that occurring during RRMS relapses. Monitoring of both sHLA‐I and sHLA‐II appears necessary if these molecules are to be developed as RRMS activity markers.

Neuroimaging in Multiple Sclerosis

The past decade has witnessed remarkable advances in our understanding of multiple sclerosis (MS), including the natural course of MS; the immunopathogenic interactive mechanisms between cerebral endothelial cells, activated CD4 T lymphocytes, macrophages, and other inflammatory mediators; and the development of new therapies that can reduce relapse rate and delay onset of disability. Undoubtedly, these achievements could not have been possible without the application of modern neuroimaging techniques. Magnetic resonance imaging (MRI) studies initiated in the 1980s have provided objective evidence of the dynamic and destructive nature of MS. Indeed, MRI and other MR techniques such as fluid attenuated inversion recovery, diffusion‐weighted imaging/ADC map, magnetic resonance spectroscopy, magnetization transfer imaging, functional MRI, diffusion tensor imaging, and single photon computed/positron emission tomography have altered our conception of MS as a purely demyelinating, immune‐mediated disease of the central nervous system (CNS) into a disease with far more complex effects on the CNS, including axonal loss and neuronal degeneration. These advanced techniques have enabled monitoring of complicated pathophysiological events, including the development of demyelinating lesions and the associated loss of oligodendrocytes, axons, and neurons. In addition, these imaging techniques have made it possible to better monitor a patients response to MS therapies. This chapter presents an extensive review of the latest developments in the neuroimaging of MS.