Sj?gren's syndrome presenting as hypokalemic paralysis due to distal renal tubular acidosis

A 57-year-old woman presented with a flaccid paralysis, muscle tenderness, and respiratory depression. Laboratory results demonstrated severe hypokalemia with hyperchloremic metabolic acidosis and abnormally acidified urine. The urinary anion gap was positive in the presence of acidemia, thus establishing the diagnosis of distal renal tubular acidosis (DRTA). The patient fully recovered after potassium and alkali replacement. Further investigation revealed Sj?gren's syndrome as the underlying cause of DRTA.     

On a dominantly inherited myopathy with tubular aggregates

A 19-year-old patient presented with exercise-related myalgia, fatigue and elevated creatine kinase levels. Histology of a muscle biopsy was characterized by the presence of very large amounts of tubular aggregates. Both his father and paternal grandfather had elevated creatine kinase and large amounts of tubular aggregates in their muscle biopsies. The aggregates consisted of closely packed vesicles and tubules filled with electron-dense material or with one to several smaller tubules. Disorders with tubular aggregates in the muscle fibres such as hyperornithinaemia with gyrate atrophy of the retina, hypokalaemic periodic paralysis, hyperkalaemic periodic paralysis, myotonia congenita, alcoholism, osteomalacic myopathy etc. have been excluded. Tubular aggregates can be found in muscle disorders characterized by exercise-induced cramps, pain and stiffness. They also represent the predominant histological feature of some familial myopathies due to a yet unidentified genetic defect. In our family, there was male-to-male transmission, confirming dominant inheritance.     

Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis

Hyperkalemic periodic paralysis (HYPP), one of several inheritable myotonic diseases, results from genetic defects in the human skeletal muscle Na+ channel. In some pedigrees, HYPP is correlated with a single base pair substitution resulting in a Met replacing Thr704 in the fifth transmembrane segment of the second domain. This region is totally conserved between the human and rat channels. We have introduced the human mutation into the corresponding region of the rat muscle Na+ channel cDNA and expressed it in human embryonic kidney 293 cells. Patch-clamp recordings show that this mutation shifts the voltage dependence of activation by 10-15 mV in the negative direction. The shift results in a persistent Na+ current that activates near -70 mV; this phenomenon could underlie the abnormal muscle activity observed in patients with HYPP.     

Improvement of the exercise test after therapy in thyrotoxic periodic paralysis

The diagnosis of periodic paralysis (PP) can be aided by demonstrating a decrease in compound motor action potential (CMAP) amplitude after several minutes of exercise. We report a case of secondary hypokalemic PP due to thyrotoxicosis in which the decrease in the CMAP amplitude after exercise dramatically improved after treatment, when a euthyroid state was achieved. The exercise test is a useful electrophysiologic means of monitoring the neuromuscular status of patients with thyrotoxic periodic paralysis prior to, and after treatment of the thyrotoxicosis.     

Cardiac involvement in neuromuscular diseases

Many neuromuscular disorders involve the heart, occasionally with overt clinical disease. Muscular dystrophies (dystrophinopathies, limb girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, Steinert's myotonic dystrophy), congenital myopathies, inflammatory myopathies and metabolic diseases (glycogenosis, periodic paralysis, mitochondrial diseases) may produce dilated or hypertrophic cardiomyopathy and heart rhythm or conduction disturbances. Furthermore the heart is commonly involved in some hereditary and degenerative diseases (Friedreich's ataxia and Kugelberg-Welander syndrome) and acquired (Guillain-Barré syndrome) or inherited (Refsum's disease and Charcot-Marie-Tooth syndrome) polyneuropathies. A cardiologist's high clinical suspicion and a simple but systematic skeletal muscle and peripheral nerve investigation, including muscle enzymes quantification, neurophysiological study and muscle biopsy, are necessary for an accurate diagnosis. In selected patients, more sophisticated biochemical and genetic analysis will be necessary. In most cases, endomyocardial biopsy is not essential for the diagnosis.     

Influence of "Polarizing" infusions on anthiarrhythmic effects of beta-blockers

The antiarrhythmic effect of practolol (0.30 mg/kg) was studied in 25 patients pretreated with infusion of glucose-insulin (GI) solution. GI solution showed an antiarrhythmic effect either after or before the beta-blocker with pH in normal range or compensated metabolic acidosis. GI infusion produced a metabolic acidosis and an arrhythmogenic effect in some cases. Practolol had no antiarrhythmic effect in patients with VPB and GI infusion raised metabolic acidosis.     

Enhanced slow inactivation by V445M: a sodium channel mutation associated with myotonia

Over 20 different missense mutations in the alpha subunit of the adult skeletal muscle Na channel have been identified in families with either myotonia (muscle stiffness) or periodic paralysis, or both. The V445M mutation was recently found in a family with myotonia but no weakness. This mutation in transmembrane segment IS6 is novel because no other disease-associated mutations are in domain I. Na currents were recorded from V445M and wild-type channels transiently expressed in human embryonic kidney cells. In common with other myotonic mutants studied to date, fast gating behavior was altered by V445M in a manner predicted to increase excitability: an impairment of fast inactivation increased the persistent Na current at 10 ms and activation had a hyperpolarized shift (4 mV). In contrast, slow inactivation was enhanced by V445M due to both a slower recovery (10 mV left shift in beta(V)) and an accelerated entry rate (1.6-fold). Our results provide additional evidence that IS6 is crucial for slow inactivation and show that enhanced slow inactivation cannot prevent myotonia, whereas previous studies have shown that disrupted slow inactivation predisposes to episodic paralysis.     

Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids

The long-term use of nondepolarizing neuromuscular blocking agents (ND-NMBA) has recently been implicated as a cause of prolonged muscle weakness, although the site of the lesion and the predisposing factors have been unclear. We report 3 patients (age 37-52 years) with acute respiratory insufficiency who developed prolonged weakness following the discontinuation of ND-NMBAs. Two patients also received intravenous corticosteroids. Renal function was normal but hepatic function was impaired in all patients, and all had acidosis. Electrophysiologic studies revealed low amplitude compound motor action potentials, normal sensory studies, and fibrillations. Repetitive stimulation at 2 Hz showed a decremental response in 2 patients. The serum vecuronium level measured in 1 patient 14 days after the drug had been discontinued was 172 ng/mL. A muscle biopsy in this patient showed loss of thick, myosin filaments. The weakness in these patients is due to pathology at both the neuromuscular junction (most likely due to ND-NMBA) and muscle (most likely due to corticosteroids). Hepatic dysfunction and acidosis are contributing risk factors.     

Endomyocardial biopsies for early detection of mitochondrial disorders in hypertrophic cardiomyopathies

An early response to metabolic acidosis is an increase in the degradation of muscle protein to provide the nitrogen needed to increase glutamine production so the kidney can excrete acid. In patients with renal insufficiency, this process may represent an example of a trade-off adaptation to uremia. It requires a hormone (glucocorticoids) and the metabolic response is maladaptive because the inability of the damaged kidney to maintain acid-base balance results in loss of muscle protein. Studies of cultured cells and rats and humans with normal kidneys demonstrate that acidosis stimulates the degradation of both amino acids and protein, which would block the normal adaptive responses to a low-protein diet (ie, to reduce the degradation of essential amino acids and protein). Evidence from studies in rats and humans with chronic uremia show that acidosis is a major stimulus for catabolism. The mechanism includes stimulation of specific pathways for the degradation of protein and amino acids. Since other catabolic conditions (eg, starvation) appear to stimulate the same pathways, understanding the mechanism in acidosis could be applicable to other conditions. Thus, the loss of lean body mass in uremia appears to be a consequence of a normal metabolic response that persists until acidosis is corrected.     

A thyrotropin-secreting pituitary adenoma as a cause of thyrotoxic periodic paralysis

We describe a patient with thyrotoxic periodic paralysis (TPP) caused by a thyrotropin-secreting pituitary adenoma. The diagnosis TPP was based on the combination of episodes of reversible hypokalaemic paralysis, hyperthyroidism and electrophysiological findings. A thyrotropin-secreting pituitary adenoma was diagnosed on the basis of endocrinological function tests and MRI of the pituitary gland. Before transsphenoidal resection of the adenoma, treatment with octreotide restored euthyroidism both clinically and biochemically. Immunocytochemistry of the pituitary adenoma was positive for TSH exclusively. Incubation with octreotide or quinagolide induced decreased TSH and alpha-subunit production by the cultured adenoma cells, in agreement with the pre-operative in vivo data. This paper is the first to describe in vivo and in vitro characteristics of a thyrotropin-secreting pituitary adenoma in a patient presenting with periodic paralysis.     

Autoradiographic studies on the uptake of 3H-noradrenaline and 3H-GABA in cultured rat cerebellum

Vasoconstriction due to parallel i.a. injections of NA were studied in subcutaneous adipose tissue and gracilis muscle preparations in dogs. The vasoconstrictor response to NA was significantly lower in adipose tissue than in muscle. Only in muscle did acidosis inhibit NA-induced vasoconstriction. The beta-receptor antagonist propranolol increased the vasoconstrictor response in adipose tissue to the level of skeletal muscle. The lack of significant inhibition of NA-induced vasoconstriction in adipose tissue may be due to the simultaneous inhibition of two opposing mechanisms-alpha-adrenergic vasoconstriction and beta-adrenergic vasodilatation. After propranolol acidosis inhibited NA-induced vasoconstriction equally in adipose tissue and muscle. The difference between adipose tissue and muscle may thus be due to a greater importance of a beta-adrenergic vasodilator mechanism in the former tissue. The metabolic response to isoprenaline was inhibited by acidosis, while the direct vasodilatation was unaffected. It is suggested that the beta-adrenergic vasodilator mechanism that is inhibited by acidosis is related to the metabolism of the tissue.     

Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD

Premature lactic acidosis during exercise in patients with chronic obstructive pulmonary disease (COPD) may play a role in exercise intolerance. In this study, we evaluated whether the early exercise-induced lactic acidosis in these individuals can be explained by changes in peripheral O2 delivery (O2). Measurements of leg blood flow by thermodilution and of arterial and femoral venous blood gases, pH, and lactate were obtained during a standard incremental exercise test to capacity in eight patients with severe COPD and in eight age-matched controls. No significant difference was found between the two groups in leg blood flow at rest or during exercise at the same power outputs. Blood lactate concentrations and lactate release from the lower limb were greater in COPD patients at all submaximal exercise levels (all P < 0.05). Leg D02 at a given power output was not significantly different between the two groups, and no significant correlation was found between this parameter and blood lactate concentrations. COPD patients had lower arterial and venous pH at submaximal exercise, and there was a significant positive correlation between venous pH at 40 W and the peak O2 uptake (r = 0.91, P < 0.0001). The correlation between venous pH and peak O2 uptake suggests that early muscle acidosis may be involved in early exercise termination in COPD patients. The early lactate release from the lower limb during exercise could not be accounted for by changes in peripheral O2. The present results point to skeletal muscle dysfunction as being responsible for the early onset of lactic acidosis in COPD.     

Two cases of severe metabolic acidosis after monitoring of evoked spinal cord potential

Evoked spinal cord potential (ESCP) elicited by direct spinal cord stimulation has been applied to monitor the spinal cord function during spinal surgery. We report here two patients who showed excessive muscle contraction and developed severe metabolic acidosis as a result of the stimulation of spinal cord to measure ESCP. These changes were prevented by vecuronium administration prior to ESCP monitoring. These results suggest that excessive muscle contraction by direct spinal cord stimulation may lead to metabolic acidosis. In conclusion, the use of a non-depolarizing muscle relaxant is recommended to prevent the adverse effects of ESCP monitoring.     

Thyroid hypokalemic periodic paralysis

An unusual presentation of thyrotoxicosis resulting in hypokalemic periodic paralysis is reported here. The patients with this disorder have very low serum potassium levels during the active phase of the disease. Very often, several months pass before the diagnosis is made. Once recognized and the thyrotoxicosis is treated, the patient does well.     

Respiration mechanics in tetraplegia

Patients with quadriplegia due to transection of the lower cervical cord show, on spirographic examination, a marked decrease in vital capacity and its two components, i.e. inspiratory capacity (i.c.) and expiratory reserve volume (ERV). The loss of IC results partly from the decreased inspiratory muscle strength consecutive to the intercostal muscle paralysis but mostly from a reduction in the distensibility of the lungs and the rib cage. The reduction in ERV is related to the paralysis of all the well-recognized muscles of expiration (abdominals, interosseous internal intercostals); however, the clavicular portion of the pectoralis major allows these patients to maintain a small ERV.     

Temporalis muscle for facial reanimation. A 13-year experience with 224 procedures

A procedure for temporalis muscle transposition was used to reanimate the paralyzed face in 219 patients. In most cases, facial paralysis had followed an operation to remove an acoustic tumor. Analysis of the results showed this procedure to be highly successful and the method of choice, alone in cases of long-standing facial paralysis or to augment the effects of facial nerve grafting or hypoglossal-facial nerve anastomosis, in reanimating the mouth. It was successful in restoring a smile to 80% of the 219 patients and provided overall improvement in mouth function in 96%. Complications occurred in 21% of patients, with the most common being infection (12% of patients). Since one of us began to use the procedure to reanimate the eye and mouth, results of temporalis muscle transposition have been improved by the following: (1) using the procedure to reanimate the mouth only; (2) performing revision surgery, most often tightening the corner of the mouth (25% of patients), as indicated; (3) transposing only the midsection of the muscle; (4) implanting a prefabricated Silastic prosthesis to fill the muscle defect; (5) when indicated, lengthening the muscle with polytef (Gore-Tex+); and (6) placing the muscle in a tunnel lateral to the superficial musculoaponeurotic system to avoid injuring the underlying facial nerve should some spontaneous recovery of facial nerve function be possible.     

Stereotaxic surgery in the hyperkinetic form of infantile cerebral palsy

The results of 67 stereotaxic operations performed in 60 patients for the hyperkinetic form of infantile cerebral paralysis are presented. The efficacy of dentatotomy is compared with that of thalamotomy. Thalamotomy is most effective in patients with hemiatetosis and choreoatetoid hyperkinesis. Dentatotomy resulted not only in a reduction of hyperkinesis, but also in a considerable alleviation of muscle spasticity. The destruction of the lateral part of nuclels dentatus caused predominantly a reduction of the muscle tone and of involuntary movements of the lower extremities, and--to a lesser degree--of the upper as well. The destruction of the medial part of the nucleus dentatus resulted in a clear reduction of muscle dystony in the trunk.     

Acetazolamide-induced nephrolithiasis: implications for treatment of neuromuscular disorders

Carbonic anhydrase inhibitors can cause nephrolithiasis. We studied 20 patients receiving long-term carbonic anhydrase inhibitor treatment for periodic paralysis and myotonia. Three patients on acetazolamide (15%) developed renal calculi. Extracorporeal lithotripsy successfully removed a renal calculus in one patient and surgery removed a staghorn calculus in another, permitting continued treatment. Renal function remained normal in all patients. Nephrolithiasis is a complication of acetazolamide but does not preclude its use.     

Vacuolar changes in neuromuscular disorders: a morphometric study

BACKGROUND: Vacuoles in muscle represent a nonspecific alternation and are found in a variety of neuromuscular disorders. To understand their significance, a morphometric study of the vacuolar formation in muscle biopsies from 340 patients was reviewed. METHODS: Vacuolar changes in muscles were found in 24 out of 340 patients with muscle biopsies. The specimens were prepared for histopathological, histochemical and electron microscopic examinations. The location, size, shape, number and content of the vacuoles were recorded. The number of fibers containing vacuoles was also assessed. RESULTS: Observed after modified Gomori trichrome stain, there were rimmed and non-rimmed vacuoles. Rimmed vacuoles were found in limb-girdle myopathy with rimmed vacuoles (5), oculopharyngeal muscular dystrophy (1). inclusion body myositis (2) and neurogenic disorder (1). These vacuoles were usually cleft-like in shape in 5-16% of muscle fibers with a diameter of 3-20 microns. An elevation of acid phosphatase activities and the presence of cytoplasmic debris suggested an autophagic process. In 15 patients with non-rimmed vacuoles, round and oval shapes with variable sizes and numbers were noted. Four with acid maltase deficiency (AMD) had numerous vacuoles containing glycogen, while three with lipid storage disease contained lipid. Interestingly, in AMD the size of the vacuoles was usually more than 10 microns in diameter, but less than 5 microns in lipid storage disease. In other diseases including polymyositis (5), Duchenne muscular dystrophy (2) and hypokalemic periodic paralysis (1), the numbers of vacuoles were usually fewer than three in each fiber. CONCLUSIONS: Vacuolar changes were not specific, but morphometric analysis of the vacuoles may provide some clues in differential diagnosis. The vacuoles were usually numerous in glycogen and lipid storage diseases, while rimmed vacuoles may be found in limb-girdle myopathy with rimmed vacuoles, oculopharyngeal muscular dystrophy, and inclusion body myositis.