Disorders of membrane channels or channelopathies.

OBJECTIVE: To review the structure and function of membrane ion channels with special emphasis on inherited nervous system channel disorders or channelopathies. RESULTS: Channels are pores in the cell membrane. Through these pores ions flow across the membrane and depolarize or hyperpolarize the cell. Channels can be classified into 3 types: non-gated, directly gated and second messenger gated channels. Among the important directly gated channels are voltage gated (Na(+), K(+), Ca(2+), Cl(-)) and ligand gated (ACh, Glutamate, GABA, Glycine) channels. Channels are macromolecular protein complexes within the lipid membrane. They are divided into distinct protein units called subunits. Each subunit has a specific function and is encoded by a different gene. The following inherited channelopathies are described. (1) Sodium channelopathies: familial generalized epilepsy with febrile seizures plus, hyperkalemic periodic paralysis, paramyotonias, hypokalemic periodic paralysis; (2) potassium channelopathies: benign infantile epilepsy, episodic ataxia type 1; (3) calcium channelopathies: episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, hypokalemic periodic paralysis, central core disease, malignant hyperthermia syndrome, congenital stationary night blindness; (4) chloride channelopathies: myotonia congenitas; (5) ACh receptor channelopathies: autosomal dominant frontal lobe nocturnal epilepsy, congenital myasthenic syndromes; (6) glycine receptor channelopathies: hyperekplexia. CONCLUSIONS: Studies of human inherited channelopathies have clarified the functions of many ion channels. More than one gene may regulate a function in a channel, thus different genetic mutations may manifest with the same disorder. The complex picture of the genetic and molecular structures of channels will require frequent updates.

Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.

CONTEXT: Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. OBJECTIVE: To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. DESIGN: The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. PATIENTS: The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. MAIN OUTCOME MEASURES: Diagnosis of probable AD. RESULTS: We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% (P < .001) lower than the total patient population or compared with patients taking other medications typically used in the treatment of hypertension or cardiovascular disease. CONCLUSIONS: There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors-lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study. Arch Neurol. 2000;57:1439-1443

Persistent vegetative state: clinical and ethical issues.

Coma, vegetative state, lock-in syndrome and akinetic mutism are defined. Vegetative state is a state with no evidence of awareness of self or environment and showing cycles of sleep and wakefulness. PVS is an operational definition including time as a variable. PVS is a vegetative state that has endured or continued for at least one month. PVS can be diagnosed with a reasonable amount of medical certainty; however, the diagnosis of PVS must be kept separate from the outcome. The patient outcome can be predicted based on etiology and age. Using outcome probabilities and etiology as criteria, patients can be subdivided in 5 groups and reasonable management guidelines can be suggested. Three levels of care can be provided to PVS patients: high technology, supportive and compassionate care. Pragmatic options for the various subgroups of patients are suggested. Management decisions will remain difficult for both the family and the health-care team. The role of the physician in these difficult cases is to share the decision-making with the family.

Hemianopic anosognosia.

In a prospective study of 32 consecutive patients with homonymous visual field defects due to ischemic infarcts we found hemianopic anosognosia (HAN), defined as the unawareness of visual loss in the homonymous hemifield (or hemiquadrant), in 20 patients (62%). HAN, although occurring predominantly in right-side lesions in 16 of 26 patients (62%) was also present in four of six patients (or 67%) with left-side lesions. This group of patients has been presented in a prior report on positive spontaneous visual phenomena. HAN was associated with somatic anosognosia in nine patients and hemineglect in 17 patients. Dissociation between somatic and hemianopic anosognosia, as well as between hemineglect and HAN, was present in several patients, indicating that these phenomena may be independent of each other. Eight patients had pure homonymous hemianopia; that is, hemianopia without cognitive, motor, or somatosensory deficits. Four of these patients (Group A) had awareness of the visual deficit, whereas three patients (Group B) had HAN. Patients in these two groups had similar anatomic lesions. Patients with phosphenes, photopsias, or visual hallucinations were usually aware of their visual field loss. We suggest that HAN is most often related to failure of discovery of the deficits, occasionally to severe visual hemineglect, sometimes to generalized cognitive impairment, or to a combination of these factors. We further conclude (1) there is no specific cortical area for conscious visual perception; (2) visual awareness is processed by a distributed network including multiple visual cortices, parietal and frontal lobes, the pulvinar, and lateral geniculate bodies (lesions localized at various nodes or centers in the network may produce similar phenomena); and (3) both hemispheres are involved in visual processing and conscious awareness.

An electrophysiological metric of activity within the ON- and OFF-pathways in humans.

Several animal studies have shown an anatomical and functional separation between the ON- and OFF-pathways in the retina and in the lateral geniculate nucleus. Psychophysical studies in humans have also documented separate pathways that process increments and decrements of light. However, at the level of the visual cortex, there is electrophysiological evidence of interactions between the ON- and OFF-pathways. In addition, psychophysical studies have shown that these pathways can exhibit differential sensitivity and be differentially adapted. These findings motivated an electrophysiological study to gather further evidence of processing within the ON- and OFF-pathways in the human visual system. Using sawtooth stimulus modulation, we measured the visual evoked potential (VEP) before and after adaptation to both rapid-on and rapid-off sawtooth stimuli. The effect of adaptation was determined by comparing the VEP response in three test conditions: without adaptation, after adaptation to the same sawtooth polarity, and after adaptation to the opposite sawtooth polarity. The results reveal a selective adaptation effect, which provides physiological evidence for separate processing of increments and decrements in the human visual system. We conclude that with appropriate stimulus parameters, the VEP can serve as an objective measure of processing within the ON- and OFF-pathways in humans.

Positive spontaneous visual phenomena limited to the hemianopic field in lesions of central visual pathways.

We prospectively studied 32 patients with ischemic infarction of the retrochiasmal visual pathways. Positive spontaneous visual phenomena (PSVP) in the blind hemifield were present in 13 patients (41%). The PSVP were subdivided into phosphenes, photopsias, visual hallucinations, palinopsia, and agitated delirium with hemianopia. PSVP were never associated with auditory or other sensory positive phenomena, except in patients with agitated delirium. Patients with photopsias, phosphenes, palinopsia, and visual hallucinations had similar lesions in MRI/CT, suggesting no anatomic area unique for these four phenomena. However, there was a significant difference in the severity of associated neurologic deficits between hemianopic patients with and without PSVP. Larger lesions destroying anteriorly located visual association areas precluded the development of PSVP, which may be related to release from inhibitory input of visual regions bordering the damaged area. Patients with the syndrome of agitated delirium and hemianopia had specific lesions involving the mesial aspect of the occipital lobe, the parahippocampal gyrus, and hippocampus.

The effects of luminance and chromatic background flicker on the human visual evoked potential.

Previous studies report that background luminance flicker, which is asynchronous with signal averaging, reduces the amplitude and increases the latency of the pattern-onset visual evoked potential (VEP). This effect has been attributed to saturation of the magnocellular (m-) pathway by the flicker stimulus. In the current study, we evaluate this hypothesis and further characterize this effect. We found that flicker had similar effects on the pattern-onset and pattern-reversal VEP, suggesting that the reversal and onset responses have similar generators. Chromatic flicker decreased latency of the chromatic VEP whereas luminance flicker increased peak latency to luminance targets. This result indicates that luminance flicker saturates a rapidly conducting m-pathway whereas chromatic flicker saturates a more slowly conducting parvocellular (p-) pathway. Finally, evoked potentials to chromatic and luminance stimuli were recorded from 34 electrodes over the scalp in the presence of static and asynchronously modulated backgrounds. An equivalent dipole model was used to assess occipital, parietal, and temporal lobe components of the surface response topography. Results showed that chromatic flicker reduced activity to a greater extent in the ventral visual pathway whereas luminance flicker reduced activity to a greater extent in the dorsal visual pathway to parietal lobe. We conclude that the VEP to isoluminant color and luminance stimuli contains both m- and p-pathway components. Asynchronous flicker can be used to selectively reduce the contribution of these pathways to the surface recorded VEP. Our results provide evidence of parallel pathways in the human visual system, with a dorsal luminance channel projecting predominantly to the posterior parietal lobe and a ventral color channel projecting predominantly to inferior temporal lobe.

Regional alterations in M1 muscarinic receptor-G protein coupling in Alzheimer's disease.

Previous studies examining the functional status of cortical muscarinic cholinergic M1 receptors have demonstrated an impairment in receptor-G protein coupling in Alzheimer's disease (AD) as measured by the inability of the receptor to form a high affinity agonist binding site. In order to investigate whether this alteration was a global phenomenon or a regional specific defect in signal transduction, we examined agonist binding at M1 receptors in three brain areas (superior frontal cortex, Brodmann areas 8 and 9; primary visual cortex, Brodmann area 17; and the dorsal striatum) within the same brain in controls and moderate to severe AD cases. Competition binding studies using the M1 antagonist 3H-pirenzepine (4 nM) in the presence of varying concentrations of the cholinergic agonist carbachol (50 nM to 1 mM) were performed in the presence and absence of GppNHp (100 microM), a non-hydrolyzable analog of GTP. In control membrane preparations, computer-assisted analysis of antagonist-agonist competition curves revealed that M1 receptor agonist binding fit a two site model with high and low affinity states in all three brain areas in the absence of GppNHp but only a single site in the presence of GppNHp. This is consistent with the ternary complex model of G protein-linked receptors. In contrast, curves obtained from both cortical regions from AD brains fit a single site model with low affinity in the presence or absence of GppNHp. On the other hand, agonist binding data obtained from the dorsal striatum of AD cases exhibited a two site fit, similar to that seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Anatomy and physiology of the visual system.

This article reviews the anatomy and physiology of the visual system. The physical stimulus is coded by several separate and parallel pathways at multiple sites in the nervous system. We outline the major parallel pathways of the system, from their beginning in the retina, to the multiple cortical areas that receive visual input. Emphasis has been placed on the functional properties of the neurons of these pathways and the various cortical processing areas as they are currently known. Clinical syndromes as a result of damage to specific visual cortical areas are also described.