SECTION I CELLULAR PHYSIOLOGY Poisoning with Saxitoxin A 30-year-old woman is brought into the emergency room.The patient had been dining in a local restaurant.and while eating dessert she noted the following symptoms.Initially there was a tingling sensation that affected the mouth and lips, but then it spread to the face and neck.Then the tingling spread down the arms and legs to the fingers and toes. At the hospital the patient reports numbness of the areas that previously tingled and difficulty walking in a coordinated fashion.The patient is asked to describe the neal she has just eaten and states that she had shrimp cocktail as an appetizer. folloved by salad,steak with a baked potato and green beans,and apple pie and coffee for dessert.The patient has no history of allergic response to shellfish.Her superficial reflexes are alrost absent.and her deep reflexes are markedly hypoactive.An extracellular electrode is placed on the patient's ulnar nerve.Then the palmar surface of the patieat's little finger is scraped with the physician's fingernail in a way that should be painful to the patiemt.The patient canmot feel this stimulus,and no action potentials are detected in the ulnar nerve.When an intracellular microelectrode is placed on a sensory nerve fiber in the ulnar nerve. the resting meabrane potential is found to be near -70 mV (normal).When an action potential is evoked by repeated vigorous scraping of the skin of the little finger as described earlier.the action potential is slower to rise and of shorter height than expected from measurements in normal individuals.The duration of the action potential is nornal. 1.What can be concluded from the failure of vigorous scraping of the skin of the little finger to elieit action potentials in the ulnar nerve? 2.What can be concluded from the gross neurologic symptoms and findings taken together?
SECTION I CELLULAR PHYSIOLOGY Poisoning with Saxitoxin A 30-year-old woman is brought into the emergency room. The patient had been dining in a local restaurant, and while eating dessert she noted the following symptoms. Initially there was a tingling sensation that affected the mouth and lips, but then it spread to the face and neck. Then the tingling spread down the arms and legs to the fingers and toes. At the hospital the patient reports numbness of the areas that previously tingled and difficulty walking in a coordinated fashion. The patient is asked to describe the meal she has just eaten and states that she had shrimp cocktail as an appetizer, followed by salad, steak with a baked potato and green beans, and apple pie and coffee for dessert. The patient has no history of allergic response to shellfish. Her superficial reflexes are almost absent, and her deep reflexes are markedly hypoactive. An extracellular electrode is placed on the patient's ulnar nerve. Then the palmar surface of the patient's little finger is scraped with the physician's fingernail in a way that should be painful to the patient. The patient cannot feel this stimulus, and no action potentials are detected in the ulnar nerve. When an intracellular microelectrode is placed on a sensory nerve fiber in the ulnar nerve, the resting membrane potential is found to be near -70 mV (normal). When an action potential is evoked by repeated vigorous scraping of the skin of the little finger as described earlier, the action potential is slower to rise and of shorter height than expected from measurements in normal individuals. The duration of the action potential is normal. 1. What can be concluded from the failure of vigorous scraping of the skin of the little finger to elicit action potentials in the ulnar nerve? 2. What can be concluded from the gross neurologic symptoms and findings taken together?
3.What can be coneluded from the finding that the resting menbrane potential in the sensory fibers in the ulmar nerve is near normal? 4.What might explain the finding that the action potential in the sensory fiber in the ulnar nerve is slow to rise and of smaller height than normal? 5.Why is the action potential in the semsory fiber of normal duration? 6.What may be the cause of this patient's difriculties? 7.How should this patient's care be managed,and what is her prognosis? ANSVER 1.The finding is consistent with depressed function of cutaneous sensory receptors or with a failure of the mechanisn by which action potentials are conducted or generated in the sensory nerve fibers. 2.The initial tingling and nurbness are consistent with a malfunction of the cutaneous sensory system.The absence of superficial reflexes and the hypoactivity of deep reflexes suggest a more widespread failure of sensory input to and possibly motor output from the central nervous system Finally,the patient's difficulty in walking.together with the other symptoas and findings,suggests a gemeralized deficit in action potential generation and/or conduction in the nervous system. 3.The finding of a normal resting potential suggests that the resting K+ conductance of the sensory nerve fiber is normal.The K+conductance is a major determinant of the resting merhrane potential.Even a small change in the resting K+conductance would result in a proportional change in the resting nenbrane potential.This finding would also seem to rule out any major change in the resting Nat conductance. 4.The finding that the action potential evoked in the semsory fiber is slower to rise and of smaller height than normal,together vith the fact that the resting potential is normal,suggests that there is a defect in the function of the Nat channels.If a smaller muher of Na+channels than normal were participating in the
3. What can be concluded from the finding that the resting membrane potential in the sensory fibers in the ulnar nerve is near normal? 4. What might explain the finding that the action potential in the sensory fiber in the ulnar nerve is slow to rise and of smaller height than normal? 5. Why is the action potential in the sensory fiber of normal duration? 6. What may be the cause of this patient's difficulties? 7. How should this patient's care be managed, and what is her prognosis? ANSWER 1. The finding is consistent with depressed function of cutaneous sensory receptors or with a failure of the mechanism by which action potentials are conducted or generated in the sensory nerve fibers. 2. The initial tingling and numbness are consistent with a malfunction of the cutaneous sensory system. The absence of superficial reflexes and the hypoactivity of deep reflexes suggest a more widespread failure of sensory input to and possibly motor output from the central nervous system. Finally, the patient's difficulty in walking, together with the other symptoms and findings, suggests a generalized deficit in action potential generation and/or conduction in the nervous system. 3. The finding of a normal resting potential suggests that the resting K+ conductance of the sensory nerve fiber is normal. The K+ conductance is a major determinant of the resting membrane potential. Even a small change in the resting K+ conductance would result in a proportional change in the resting membrane potential. This finding would also seem to rule out any major change in the resting Na+ conductance. 4. The finding that the action potential evoked in the sensory fiber is slower to rise and of smaller height than normal, together with the fact that the resting potential is normal, suggests that there is a defect in the function of the Na+ channels. If a smaller number of Na+ channels than normal were participating in the
action potential,a slower rate of rise and a smller amplitude of the action potential would be expected. 5.The delayed opening of K+channels and the voltage-inactivation of the Na+ channels are the major determinants of the duration of the action potential.The finding that the action potential is of approximately normal duration suggests that there is nothing abnormal about the kinetics of opening of the K+channels and that the voltage dependence and time dependence of the inactivation of Na+chamnels are not abnormal.This,together with the reduced rate of rise and amplitude of the action potential,sugcests that those Na+channels that are activated are functioning normally,but that a fraction of the Na+channels fails to open in response to merbrane depolarization. 6.The rapid onset (about 30 minutes)of the patient's symptons,as well as the patient's neurologic deficits,are nost consistent with a disorder knowm as paralytic shellfish poisoning.A toxin (saxitoxin)present in shellfish under some circunstances can cause these symptoms.Saxitoxin has actions similar to those of tetrodotoxin (the toxin from puffer fish).Saxitoxin blocks the opeming of voltage-gated Na+channels in an all-or-nome fashion.Saxitoxin is produced by certain dimoflagellates of the genus Conyaulax.Shellfish that feed on these dinoflagellates concentrate the toxin in their tissues.Then the dinoflagellates are abundant,they are responsible for the red tide,so-called because of reddish pignents they contain.Fishermen and public health officials have learned that shellfish should not be harvested during a bloom of these dinoflagellates,as indicated by a red tide.It is still not understood why the nerves and muscles of the shellfish are seemingly unaffected by levels of saxitoxin that are lethal to a】级. 7.Yictins of paralytic shellfish poisoning sometimes die.When they do,it is hecause of paralysis of the respiratory muscles.After about 12 hours,if the victin has not experienced respiratory paralysis,the prognosis is quite good.Thus the patient should be monitored continuously for at least 12 hours so that mechanical
action potential, a slower rate of rise and a smaller amplitude of the action potential would be expected. 5. The delayed opening of K+ channels and the voltage-inactivation of the Na+ channels are the major determinants of the duration of the action potential. The finding that the action potential is of approximately normal duration suggests that there is nothing abnormal about the kinetics of opening of the K+ channels and that the voltage dependence and time dependence of the inactivation of Na+ channels are not abnormal. This, together with the reduced rate of rise and amplitude of the action potential, suggests that those Na+ channels that are activated are functioning normally, but that a fraction of the Na+ channels fails to open in response to membrane depolarization. 6. The rapid onset (about 30 minutes) of the patient's symptoms, as well as the patient's neurologic deficits, are most consistent with a disorder known as paralytic shellfish poisoning. A toxin (saxitoxin) present in shellfish under some circumstances can cause these symptoms. Saxitoxin has actions similar to those of tetrodotoxin (the toxin from puffer fish). Saxitoxin blocks the opening of voltage-gated Na+ channels in an all-or-none fashion. Saxitoxin is produced by certain dinoflagellates of the genus Gonyaulax. Shellfish that feed on these dinoflagellates concentrate the toxin in their tissues. When the dinoflagellates are abundant, they are responsible for the red tide, so-called because of reddish pigments they contain. Fishermen and public health officials have learned that shellfish should not be harvested during a bloom of these dinoflagellates, as indicated by a red tide. It is still not understood why the nerves and muscles of the shellfish are seemingly unaffected by levels of saxitoxin that are lethal to mammals. 7. Victims of paralytic shellfish poisoning sometimes die. When they do, it is because of paralysis of the respiratory muscles. After about 12 hours, if the victim has not experienced respiratory paralysis, the prognosis is quite good. Thus the patient should be monitored continuously for at least 12 hours so that mechanical
ventilation can be established immediately should the patient cease breathing on her own.Typically,complete recovery fron the symptons of saxitoxin poisoning may require 24 bours or pore.The slow recovery is the result of the extremely tight binding of the toxin to Nat channels (the dissociation constant is in the low nanomolar range).For this reason the toxin only slowly dissociates from the Na+ channels so that it can be excreted in the urine
ventilation can be established immediately should the patient cease breathing on her own. Typically, complete recovery from the symptoms of saxitoxin poisoning may require 24 hours or more. The slow recovery is the result of the extremely tight binding of the toxin to Na+ channels (the dissociation constant is in the low nanomolar range). For this reason the toxin only slowly dissociates from the Na+ channels so that it can be excreted in the urine