Paralysis

			Paralysis is the complete loss of muscle function for one or more muscle groups. Paralysis often includes loss of feeling in the affected area.

Causes
Paralysis is most often caused by damage to the nervous system or brain, especially the spinal cord. Partial paralysis can also occur in the REM stage of sleep. Major causes are stroke, trauma, poliomyelitis, amyotrophic lateral sclerosis (ALS), botulism, spina bifida, multiple sclerosis, and Guillain-Barré syndrome. Poisons that interfere with nerve function, such as curare, can also cause paralysis.

Variations
Paralysis may be localized, or generalized, or it may follow a certain pattern. For example, localized paralysis occurs in Bell's palsy where one side of the face may be paralyzed due to inflammation of the facial nerve on that side. Patients with stroke may be weak throughout their body (global paralysis) or have hemiplegia (weakness on one side of the body) or other patterns of paralysis depending on the area of damage in the brain. Other patterns of paralysis arise due to different lesions and their sequelae. For example, lower spinal cord damage from a severe back injury may result in paraplegia, while an injury higher up on the spinal cord, such as a neck injury, can cause quadriplegia. Patients with paraplegia or quadriplegia often use equipment such as a wheelchair or standing frame for mobility and to regain some independence.

Most paralyses caused by nervous system damage are constant in nature; however, there are forms of periodic paralysis, including sleep paralysis, which are caused by other factors.

"Paralysis occurs only when the patient is at rest, and usually in bed at night. The rest commonly follows a period of unusually great physical activity and consumption of a high-carbohydrate meal. Observant patients, realizing that paralysis did not occur while they were active, rapidly learn to "work off" an impending attack on the appearance of premonitory symptoms."

Etiology
Patients with thyrotoxic periodic paralysis have attacks only when they are thyrotoxic. Graves' disease appears to be the most common cause of thyrotoxic periodic paralysis, since this disorder represents the majority of patients with hyperthyroidism. However, it appears that the specific cause of the thyrotoxic state is not a critical factor for the expression of the paralytic attacks because cases have been documented in association with jodbasedow, TSH-secreting pituitary tumor,abuse of thyroid hormone, and solitary toxic thyroid adenoma. These associations of paralysis with the different causes of thyrotoxicosis indicate that the attacks are induced in susceptible persons by a mechanism that is not autoimmune in origin. Paralytic attacks can be induced by insulin and carbohydrate administration in hyperthyroid patients with a history of thyrotoxic periodic paralysis but not in patients with a history of thyrotoxic periodic paralysis who have become euthyroid.Restoring the euthyroid state in patients with a history of thyrotoxic periodic paralysis usually prevents the recurrence of paralytic attacks. However, paralytic attacks recur if thyrotoxicosis recurs.[2,25] In comparing thyrotoxic patients with recurrent paralytic attacks and those without such episodes, it was noted that the occurrence of paralysis was not related to the duration and severity of the thyrotoxicosis.

Epidemiology
Thyrotoxic periodic paralysis is most commonly described among Asian men. Of the 1,366 consecutive cases of thyrotoxicosis in southern Chinese patients, 1.8% gave a history of attacks of paralysis. Case reports from the Mayo Clinic indicated that the approximate incidence for thyrotoxic periodic paralysis in a largely North American population ranged from 0.1% to 0.2%, or about one tenth the rate reported for Asian populations. A review by Ober of cases from the continental United States showed the distribution of thyrotoxic periodic paralysis is 45% white, 24% Asian, 15.5% Hispanic, 7% black, 7% American Indian, and 1% others. Review of the literature indicates that the occurrence of thyrotoxic periodic paralysis is very rare among blacks. Our cases represent the ninth and tenth reported cases in black patients.
Thyrotoxic periodic paralysis primarily afflicts men. In the review of 1,366 cases of hyperthyroidism in southern Chinese patients, 13% of the men and 0.17% of the women had thyrotoxic periodic paralysis.Of the known factors that provoke the onset of paralysis, it might be suggested that physical exertion would be greater in men. However, a large number of Chinese women are engaged in heavy manual labor, making the degree of physical exertion a less important precipitating factor. In the cases among black patients, including our 2 cases, eight patients were men and only two were women.

Pathophysiology
Although the mechanism of thyrotoxic periodic paralysis remains uncertain, the two main ingredients that produce a paralytic attack are thyrotoxicosis and hypokalemia. It has been shown[32] that Na+,K+-ATPase activity in patients with thyrotoxic periodic paralysis was significantly higher than in healthy subjects or in thyrotoxic patients without a history of paralysis despite similar degree of hyperthyroidism. Compared with thyrotoxic patients without paralysis, patients with thyrotoxic periodic paralysis respond to thyrotoxicosis with a smaller decrement in erythrocyte Na+,K+-ATPase activity, however, the difference is too small to represent a useful genetic marker for this disease entity.There are high levels of immunoreactive insulin during spontaneous attacks in thyrotoxic periodic paralysis. An increase in plasma glucose concentration together with abnormally high levels of serum immunoreactive insulin was observed preceding a spontaneous attack of paralysis, and the affinity of erythrocyte insulin receptors was decreased during the attack.] In thyrotoxic periodic paralysis, patients have been found to have hyperinsulinemia, and this is accompanied by increased Na+,K+-ATPase activity. Precipitation of an attack by a carbohydrate diet was associated with only a modest fall in level of plasma potassium but with a marked rise in total blood cell potassium.
It has been observed that b-blockade with propranolol prevents paralysis, and this suggests that the development of paralysis is partly influenced by the hyperadrenergic state characteristic of thyrotoxicosis. Studies in skeletal muscle have shown that CA++-ATPase activity and the calcium uptake by sarcoplasmic reticulum decrease during the attack of paralysis but revert to normal after the attack.[39] The decrease in the activity of the calcium pump was proportional to the severity of paralysis and the degree of hypokalemia.

Studies suggest that chronically elevated plasma aldosterone levels may contribute to the occurrence of periodic paralysis of thyrotoxicosis in some patients, especially when further stimulated by a prompt increase in endogenous corticotropin as the result of severe stress, or even a normal or diurnal rise. In 17 hyperthyroid patients without paralysis, neurophysiologic evaluation of untreated hyperthyroid patients showed abnormalities mainly in the proximal muscles, and these findings suggest the presence of an initial axonal type of mild polyneuropathy.In a study of 7 patients with thyrotoxic periodic paralysis by using glucose and insulin infusion, a paralytic attack developed within 90 minutes in 6 of 7 patients.These results suggest that hyperaldosteronism may not be a trigger for the induced paralytic attack but may be a phenomenon due to volume depletion and a change in potassium homeostasis induced by glucose and insulin infusion.

Electromyographic studies in eight Chinese patients with thyrotoxic periodic paralysis showed that most had a myopathic pattern during an attack of paralysis that disappeared during remission.The myopathic changes were a decrease in duration of muscle action potentials, an increase in polyphasic potentials, a satisfactory interface pattern with reduced amplitude, and a reduced amplitude of the evoked muscle action potential on nerve stimulation. Peripheral nerve function was normal in these cases, and it was concluded that the weakness in thyrotoxic periodic paralysis is myopathic and that the peripheral nerve function during paralysis is normal.

Light microscopy of the biopsied quadriceps muscles during paralysis in 17 patients with thyrotoxic periodic paralysis showed no abnormalities in 23.5%, sarcolemmal nuclear proliferation in 35.5%, atrophy of muscle fibers in 29.4%, central nuclei in 23.5%, fatty infiltration in 17.6%, vacuolation in 11.8%, and sarcoplasmic masses in 11.8%. These muscles were also examined by electron microscopy in 10 patients; the main changes observed were vacuolation in 90%, mitochondrial abnormalities in 100%, glycogen granules accumulation in 100%, disruption of the myofibers in 50%, and changes in the T system in 40%.The light and electron microscopic changes in the skeletal muscles during paralysis were not well-correlated with the severity of the muscle weakness of hypokalemia.

In another study, electron microscopic examination of muscle biopsy specimens made it possible to assume that in thyrotoxic periodic paralysis, the action of the thyroid hormone not only causes impairment of the mineral metabolism, but also brings about changes in the structure of the membranes of the sarcolemma and T system, which leads to disturbances of conductance of action potential into the fiber. These changes affect the function of the end cisterns and lead to distortion of the processes of conjugation of excitation-contraction with resulting development of paresis and paralysis of muscles.

In animal studies, thyroid hormone appears to regulate Na channels in cultured rat skeletal myotubes by two opposing mechanisms, (1) direct stimulation of Na channel synthesis and (2) indirect decrease in synthesis mediated by an increase in cytosolic Ca[2]+. The results indicate that thyroid hormone may play an important role in developmental expression of Na channels in excitable tissue. In rats, triiodothyronine induced upregulation of the concentration on Na+ channels and Na+,K+ pumps, which was associated with a progressive loss of contractile endurance. These observations are important for an understanding of the fatigue associated with hyperthyroidism and add further support to the hypothesis that muscle endurance depends on the leak-to-pump ratio for Na+. In rat soleus muscle, thyroid hormone at physiologic doses seems to be the major endocrine factor determining the concentration of Na+,K+ pumps in skeletal muscle, and endurance is a function of the ratio between the concentration of Na+ channels and Na+,K+ pumps. In rat skeletal muscle, the stimulation of the Na/H antiport by physiologic concentrations of thyroid hormones results in a dose-dependent increase in intracellular pH.These findings suggest that thyroid hormones may have an active role in the recovery from muscular acidosis through direct stimulation of the Na/H antiport.

Studies of the interaction of the thyroid state and skeletal myosin heavy chain expression in rats suggest that for patients with nerve damage and/or paralysis, both muscle mass and biochemical properties can also be affected by the thyroid state. In rat heart, the status of sarcolemmal Ca[2]+ transport processes is regulated by thyroid hormones, and the modification of Ca[2]+ fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.In hyperthyroid cats with hypokalemia and skeletal muscle weakness manifested as ventroflexion of the neck, correction of the hypokalemia led to recovery in muscle strength.

In the rat brain, Na+,K+-ATPase activity has been noted to be significantly greater in males than in females, and testosterone induces an increase in the Na+,K+-ATPase activity. Other studies in rats showed that hepatic Na+,K+- ATPase activity is inhibited by estrogen. Progesterone or progesterone derivatives also inhibited Na+,K+-ATPase activity in the canine kidney and in the guinea pig heart and brain.These effects of sex hormones on the Na+,K+ pump may contribute to the predisposition for thyrotoxic periodic paralysis in men.

Genetics
Unlike familial hypokalemic periodic paralysis, thyrotoxic periodic paralysis is not usually associated with family history. There is, however, an association with the presence of HLA-DRw8, and data suggest that this gene may play a significant role in the susceptibility to thyrotoxic periodic paralysis among Japanese men. In a pair of monozygous adolescent male twins with hyperthyroidism, one had thyroiditis while the other had muscle weakness and paralysis. The finding of HLA antigens A2BW22 and AW19B17 in Chinese patients with thyrotoxic periodic paralysis but not in patients without the disorder raises the possibility that these haplotypes may serve as genetic markers. In a black patient, phenotyping revealed neither of the two genetic markers previously observed among Chinese patients with thyrotoxic periodic paralysis, indicating that the haplotypes do not serve as markers for the disorder in black patients. Although the HLA system has been suggested to provide a link to a presumed immunogenetic etiology of the thyrotoxic periodic paralysis, this seems to be an unlikely explanation in view of the numerous patients with the disorder whose thyrotoxicosis is not related to autoimmune mechanism. The high incidence of the disorder in Asians suggests that the basic defect may be genetically determined, but the defect manifests itself only when challenged by thyrotoxicosis.

Treatment
The definitive therapy for thyrotoxic periodic paralysis is the management of the thyrotoxic state by medical therapy, surgery, or radioactive iodine therapy. The resolution of periodic paralysis with restoration of euthyroidism has been acknowledged as a universal finding.The Na+,K+-ATPase activity in RBCs was found to be impaired in Graves' disease, and thioamide treatment restored the normal activity. One case was an exception, however, because the periodic paralysis persisted even when the patient's clinical and laboratory features suggested a euthyroid state. This patient continued to have symptoms of periodic paralysis when he progressed to hypothyroidism after radioactive iodine ablation.
Once the paralytic attack has started, administration of potassium is standard therapy, and recovery of the periodic paralysis may be hastened. Although the serum potassium level will eventually normalize spontaneously as potassium moves from the intracellular space to the extracellular space, the administration of potassium is not done to correct the hypokalemia. It is given mainly to prevent cardiac arrhythmias that potentially can be life-threatening. Potassium is usually administered intravenously, even though there is no proven benefit or advantage in using this method of administration.

As potassium is released from the cells into the circulation during the recovery phase of the paralytic attack, aggressive potassium administration can lead to hyperkalemia, as happened in our case 2 patient with a potassium level of 6.1 mmol/L after receiving a dose of only 60 mEq KCl. A patient who had a potassium level of 1.9 mEq/L progressed to a level of 6.4 mEq/L after receiving 100 mEq KCl intravenously over 10 hours.20 In cases with associated hypophosphatemia, as in our patients' cases and those of Norris et al and Guthrie et al, it has been observed that serum phosphate levels returned to normal after giving only potassium.

After initiating the definitive therapy for the thyrotoxicosis, patients should be advised to avoid precipitating factors while awaiting normalization of the thyrotoxic state. Others have advocated supplementation with oral potassium to prevent attacks of paralysis in some patients, though this approach is not consistently effective. Acetazolamide has been used in the familial hypokalemic periodic paralysis; however, in one case a Hispanic man was given acetazolamide for his thyrotoxic periodic paralysis, which had been mistakenly diagnosed as familial hypokalemic periodic paralysis, and this resulted in near-total body paralysis 2 weeks later. In some cases, the efficacy of using spironolactone or aldosterone antagonist SC942065 in preventing paralytic attacks is well-documented. b-Adrenergic blockade induced with propranolol therapy has resulted in marked relief of the episodes of paralysis and is probably the most useful preventive therapy until a euthyroid state is achieved.

Paralysis in the animal world
Many species of animals use paralyzing toxins in order to capture prey, evade predation, or both. One famous example is the tetrodotoxin of fish species such as Takifugu rubripes, the famously lethal pufferfish of Japanese fugu. This toxin works by binding to sodium channels in nerve cells, preventing the cells' proper function. A non-lethal dose of this toxin results in temporary paralysis. This toxin is also present in many other species ranging from toads to nemerteans. Another interesting use of paralysis in the natural world is the behavior of some species of wasp. In order to complete the reproductive cycle, the female wasp first paralyzes a prey item such as a grasshopper and then places it into her nest. Eggs are then laid on the paralyzed insect, which is devoured by the larvae after they hatch. Many snakes also exhibit powerful neurotoxins that can cause non-permanent paralysis or death.

Paralysis can be seen in breeds of dogs that are chondrodysplastic. These dogs have short legs, and may also have short muzzles. Their intervertebral disc material can calcify and become more brittle. In such cases, the disc may rupture, with disc material ending up in the spinal canal, or rupturing more laterally to press on spinal nerves. A minor rupture may only result in paresis, but a major rupture can cause enough damage to result in complete paralysis. If no signs of pain can be elicited, surgery should be performed within 24 hours of the incident, to remove the disc material and relieve pressure on the spinal cord. After 24 hours, the chance of recovery declines rapidly, since with continued pressure, the spinal cord tissue deteriorates and dies.

Another type of paralysis is caused by a fibrocartilaginous embolism. This is a microscopic piece of disc material that breaks off and becomes lodged in a spinal artery. Nerves served by the artery will die when deprived of blood. The German Shepherd is especially prone to developing degenerative myelopathy. This is a deterioration of nerves in the spinal cord, starting in the posterior part of the cord. Dogs so affected will become gradually weaker in the hind legs as nerves die off. Eventually their hind legs become useless. They often also exhibit fecal and urinary incontinence. As the disease progresses, the paresis and paralysis gradually move forward. This disease also affects other large breeds of dogs. It is suspected to be an autoimmune problem.

Cats with heart murmurs may develop blood clots which travel through arteries. If the clot is large enough to block one or both femoral arteries, there may be hind leg paralysis because the major source of blood flow to the hind leg is blocked.

This page was last modified 09.10, 10 Febuary 2008.

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