Philip G. McManis

Dihydropyridine Receptor Mutations Cause Hypokalemic Periodic Paralysis

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant skeletal muscle disorder manifested by episodic weakness associated with low serum potassium. Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31-q32 near a dihydropyridine (DHP) receptor gene. This receptor functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner. We have characterized patient-specific DHP receptor mutations in 11 probands of 33 independent hypoKPP kindreds that occur at one of two adjacent nucleotides within the same codon and predict substitution of a highly conserved arginine in the S4 segment of domain 4 with either histidine or glycine. In one kindred, the mutation arose de novo. Taken together, these data establish this DHP receptor as the hypoKPP gene. We are unaware of any other human diseases presently known to result from DHP receptor mutations.

Nerve Blood Flow and Oxygen Delivery In Normal, Diabetic, and Ischemic Neuropathy

Publisher Summary The chapter discusses that in experimental ischemic neuropathy caused by exsanguination, the reduction in blood flow velocity is the major factor reducing endoneurial oxygen delivery. The chapter also presents that in arterial hypoxemia caused by reduced oxygen content of inspired air, the effects of reduced arterial oxygen tension (arterial hypoxia) are supplemented by effects of reduced blood flow (venous hypoxia) caused by reduction in cardiac output due to cardiac muscle hypoxia. In experimental edematous neuropathy (e.g., galactose neuropathy), the increased intercapillary distance is a major factor in reducing the oxygen supply. The adverse effects of increased intercapillary distance are partially offset, however, by a reduced oxygen consumption rate per unit volume of tissue that results from the effects of edema, because much of the increase in nerve volume is due to accumulation of extracellular fluid that is not metabolically active. Mathematical models of the release of oxygen from hemoglobin and its diffusion from capillaries to surrounding tissue have been applied to skeletal muscle, cardiac muscle and brain.

Sodium channel mutations in acetazolamide‐responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis

Hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.

Randomized trials of dichlorphenamide in the periodic paralyses

Although the carbonic anhydrase inhibitors have been used in the treatment of the primary periodic paralyses (PPs), their efficacy has not been demonstrated in double‐blind, placebo‐controlled trials. Therefore, we tested the efficacy of dichlorphenamide (DCP; Daranide), a potent carbonic anhydrase inhibitor, in the treatment of episodic weakness in the primary PPs. We performed two multicenter, randomized, double‐blind, placebo‐controlled crossover trials, one involving 42 subjects with hypokalemic periodic paralysis (HypoPP) and the other involving 31 subjects with potassium‐sensitive periodic paralysis (PSPP). In each trial, two 8‐week treatment periods were separated by an active washout period of at least 9 weeks. The primary outcome variable in the HypoPP trial was the occurrence of an intolerable increase in attack severity or frequency (end point). The primary outcome variable in the PSPP trial was the number of attacks per week. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP. Ann Neurol 2000; 47:46–53

Laboratory findings in reflex sympathetic dystrophy: a preliminary report.

Objective:The purpose of our study was to compare sudomotor and vasomotor indices in patients with clinical reflex sympathetic dystrophy. Design:Vsomotor tone was determined by measuring skin blood flow with laser Doppler flowmeters and skin temperature by infrared thermomety. Resting and evol ked sweat output was measured with the quantitative sudomotor axon reflex test. Control values were determined from studies on 223 normal subjects. Setting:The setting was a tertiary/academic medical center. Patients:There were 12 patients with clinical reflex sympathetic dystrophy in an extremity. Main Outcome Measures:These were skin vasomotor tone and evoked sweat output. Results:Resting sweat output asymmetry was seen in 67% of patients, quantitative sudomotor axon reflex test asymmetry was seen in 75%, and vasomotor changes in 80%. When sudomotor and vasomotor indices were combined, abnormalities were seen in all patients. Conclusions:Laboratory quantitation of autonomic indices enhances the clinical evaluation of patients with reflex sympathetic dystrophy.

Neuropathy associated with hyperlipidemia

We describe six patients with painful polyneuropathy associated with hyperlipidemia. Each had mild, slowly progressive neuropathy characterized by pain in feet, without proximal extension or involvement of hands. Weakness and autonomic symptoms and signs were absent. Three patients had normal tendon reflexes; three others had decreased ankle reflexes. Serum cholesterol levels were moderately increased; serum triglyceride levels were exceedingly high. In one patient, symptoms resolved with correction of hypertriglyceridemia. No other cause of peripheral neuropathy was found. Marked increases in serum triglycerides may cause painful small-fiber neuropathy.

Factors affecting the relative viability of centrifascicular and subperineurial axons in acute peripheral nerve ischemia.

An acute reduction in nerve blood flow commonly results in centrifascicular fiber degeneration with subperineurial fiber sparing (CD-SS pattern) in experimental and human peripheral nerve. The mechanism of CD-SS pattern is uncertain. Three hypotheses for the better resistance to ischemic degeneration of subperineurial fibers have been suggested. The subperineurial region has been proposed to have (i) better anastomotic flow (ii) an increased capillary density, or (iii) an extra source of oxygen (from surrounding tissue). We developed methodology that permitted testing of these hypotheses. Nerve blood flow and oxygen tension were measured simultaneously in the central and subperineurial regions using microelectrodes and polarographic techniques. The longitudinal distribution of nerve blood flow was also determined. To test the first hypothesis, nerve blood flow was measured before and after arterial ligation. Well defined watershed areas of reduced flow were found in the longitudinal axis. However, even within these zones, there was a uniform rather than a differential radial reduction in nerve blood flow resulting from ligation. To test the second hypothesis, nerve blood flow was measured during induced arterial hypotension. Nerve blood flow was reduced in proportion to the severity of the ischemic insult but there was no physiologically significant difference between the central and subperineurial areas. To test the oxygen diffusion hypothesis, nerve oxygen tension was monitored simultaneously in the two sites at rest and during ischemia produced by arterial hypotension. Arterial hypotension resulted in severe centrifascicular hypoxia whereas subperineurial oxygen tension was much better maintained as a result of diffusion of oxygen into nerve from the surrounding pool of oil. These findings strongly suggest that the sparing of subperineurial axons in ischemic nerve trunks is due to the diffusion of oxygen from surrounding viable tissues rather than greater capillary density or anastomotic flow.

Sciatic nerve lesions during cardiac surgery

Sciatic nerve lesions occur only rarely in cardiac surgery patients. To evaluate potential causes for sciatic neuropathy, we reviewed the cardiac surgery performed at one institution during the last 15 years and found only six instances of sciatic neuropathy. We examined medical records for these six patients for potential etiologic factors and determined that four of the six patients had undergone prolonged periods of intra-aortic balloon pump therapy with a catheter placed through the femoral artery ipsilateral to the sciatic nerve lesion, and the other two patients had an ipsilateral femoral artery occlusion. In addition, four of the six patients had severe symptomatic peripheral vascular disease, and one of the other patients had severe and prolonged perioperative hypoxia. Although all these patients had pure sciatic neuropathy clinically, two of the four patients studied with electromyography had evidence of damage to the femoral nerve or quadriceps muscles ipsilaterally. In addition to the neurogenic changes, there were electromyographic findings suggestive of muscle ischemia. These results indicate that patients undergoing cardiac surgery may be at risk for development of a sciatic neuropathy if they have compromised blood flow through the femoral artery together with another cause for tissue hypoxia. Furthermore, asymptomatic ischemia of the femoral nerve or quadriceps muscles may occur in this clinical setting.

Trigeminal sensory neuropathy associated with decreased oral sensation and impairment of the masseter inhibitory reflex

We describe 4 patients with severe trigeminal sensory neuropathy whose main disability resulted from impaired intraoral sensation associated with disturbances of mastication and swallowing. Each patient had an abnormal blink reflex and jaw jerk. In addition, the masseter inhibitory reflex was absent in 3 patients and abnormal in the 4th. This reflex plays a role in the reflex control of mastication and can easily be elicited in normal subjects by stimulation of the skin and mucous membrane in the distribution of the 2nd and 3rd divisions of the trigeminal nerve while the jaw-closing muscles are contracting. Disturbed intraoral sensation combined with impaired trigeminal reflexes (particularly the masseter inhibitory reflex) interferes with neural mechanisms that regulate chewing and can be a source of severe disability in patients with trigeminal sensory neuropathy.

Focal Periodic Myogenic Artifact Affecting the EEG

ABSTRACT.Myogenic artifacts in EEG recordings usually have no diagnostic significance, but they occasionally may have important clinical implications. We observed an unusual type of focal periodic myogenic activity (FPMA) affecting the EEG and sought to determine its clinical correlations. The EEG recordings and medical records of 22 patients with FPMA were reviewed. The FPMA consisted of single or brief groups of motor unit potentials firing periodically at rates of 2 to 7 Hz. It usually was confined to one electrode position and persisted throughout an entire record during wakefulness and sleep. Needle electrode examination confirmed the myogenic nature of the discharges in several patients. The EEG activity varied among the patients. FPMA was not associated with any concomitant epileptiform activity. Of the 22 patients, 16 were male and 6 were female. Their average age was 62.5 years (range, 11 to 82 years). No consistent underlying clinical or radiologic abnormalities were found. The data suggest that...