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1 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
BOTULISM
Definition
Botulism is an acute, progressive condition caused by botulinum toxin, a natural poison
produced by the spore-forming bacteria Clostridium botulinum. Exposure to the
botulinum toxin usually occurs from eating contaminated food although, in infants, it
may be caused by specific types of clostridia obtained from soil or inhaled spores,
causing growth of the bacteria in the infant's intestine. Botulinum toxin is a neurotoxin
that blocks the ability of motor nerves to release acetylcholine, the neurotransmitter that
relays nerve signals to muscles, a process that may result in unresponsive muscles, a
condition known as flaccid paralysis. Breathing may be severely compromised in
progressive botulism because of failure of the muscles that control the airway and
breathing.
Cause-Clostridium botulinum --------- Neurotoxin—acts on peripheral nervous system.
It is a gram positive bacillus
.
Description
Botulism occurs only rarely, but its high fatality rate makes it a great concern for those in the
general public and in the medical community. Clinical descriptions of botulism reach as far back
in history as ancient Rome andGreece. However, the relationship between contaminated food and
botulism was not defined until the late 1700s. In 1793 the German physician, Justinius Kerner
(1786–1862), deduced that a substance in spoiled sausages, which he called wurstgift (German for
sausage poison), caused botulism. The toxin's origin and identity remained vague until Emile van
Ermengem (1851–1932), a Belgian professor, isolated Clostridium botulinum in 1895 and identified
it as the source of food poisoning .
Three types of botulism have been identified: food-borne, wound, and infant botulism. The main
difference between types hinges on the route of exposure to the toxin. Food-borne botulism
accounts for 25 percent of all botulism cases and can usually be traced to eating contaminated
home-preserved food. Infant botulism accounts for 72 percent of all cases. About 98 percent of
infants recover with proper treatment. Although domestic food poisoning is a problem worldwide,
concern is growing regarding the use of botulism toxin in biological warfare. At the end of the
twentieth century 17 countries were known to be developing biological weapons, including the
culture of botulism toxins.
2 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
Types ---1.Food borne 2.Infant
3.Wound borne 4.Undertermined
Cause of death---- pulmonary copmplication
Vital capacity is more sensitive indicator than ABG.
A)Pneumonia B)Respiratory failure
Physical factors of C.botulinum:
The toxins---- heat liable ,destroyed 10—20 min in 80c
The spores –germinate in:
1.An anerobic environment
2.Adequate water and nutrient
3.Low acidity ph 4.6
4.Tem less than 4c
Source:
1.Wound
2.Food- improbably processed or stored and may be within normal taste.
Transmission
Botulism is not spread from one individual to another, but through exposure to the deadly botulinum toxin, a
natural poison produced by certain Clostridium bacteria that may be found in preserved, especially canned,
foods and sometimes in the intestines of infants. Botulism spores can cause widespread illness if introduced
into the environment.
Pathophysiology:
Ingestion of the toxin in the food
Absorption in small intestine
Distributed by lymphatic and circulatory systems
Reaches the peripheral nervous system and inhibit ACH release
Bound to presynaptic membrane
3 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
Clinical features:
When did the bacteria become pathogenic?
Toxins produced by the bacterium Clostridium botulinum are the main culprit in botulism. Other members of
the Clostridium genus can produce botulinum toxin, namely C. argentinense, C. butyricum, and C. baratii, but these are
minor sources. To grow, these bacteria require a low-acid, oxygen-free environment that is warm (40–120°F or 4.4–48.8°C)
and moist. Lacking these conditions, the bacteria transform themselves into spores that, like plant seeds, can remain
dormant for years. Clostridia and their spores exist all over the world, especially in soil and aquatic sediments. They do
not threaten human or animal health until the spores encounter an environment that favors growth. The spores then
germinate, and the growing bacteria produce the deadly botulism toxin.
How many toxins the bacteria have?
Scientists have discovered that clostridia can produce at least seven types of botulism toxin, identified as A, B, C, D, E, F,
and G. Humans are usually affected by A, B, E, and very rarely F; infants are affected by types A and B. Domesticated
animals such as dogs, cattle, and mink are affected by botulism C toxin, which also affects birds and has caused massive
die-offs in domestic bird flocks and wild waterfowl. Botulism D toxin can cause illness in cattle, and horses succumb to
botulism A, B, and C toxin. There have been no confirmed cases of human or animal botulism linked to the G toxin.
4 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
Duration of onset of symptoms:
After ingestion ---- 8 hours to 8 days
The shorter the duration , the sever the symptoms.
In humans, botulinum toxin latches onto specific proteins in nerve endings and irreversibly destroys them. These proteins
control the release of acetylcholine, a neurotransmitter that stimulates muscle cells. With acetylcholine release blocked,
nerves are not able to stimulate muscles. Ironically, this action of the botulinum toxin has given it a beneficial niche in the
world of medicine. Certain medical disorders are characterized by involuntary and uncontrollable muscle contractions.
Medical researchers have discovered that injecting a strictly controlled dose of botulinum toxin into affected muscles
inhibits excessive muscle contractions. The muscle is partially paralyzed and normal movement is retained.
ClinicalIy:
Food-borne botulism. Food that has been improperly preserved or stored can harbor botulinum toxin-producing
clostridia. Canned or jarred baby food has also been known to cause botulism. Symptoms of food-borne
botulism typically appear within 18 to 36 hours of eating contaminated food, with extremes of four hours to
eight days. Initial symptoms include blurred or double vision and difficulty swallowing and speaking. Possible
gastrointestinal problems include constipation , nausea , and vomiting . As botulism progresses, the victim
experiences weakness or paralysis, starting with the head muscles and progressing down the body. Breathing
becomes increasingly difficult. Without medical care, respiratory failure and death are very likely.
BOTULISM SHOULD BE SUSPECTED IN PATIENT WHO DEVELOP BILATERAL CRANIAL NERVE IMPAIRMENT WITH
DESCENDING PARALYSIS OF THE LIMBS AND WEAKNESS.
SYMPTOMS: (( A AND B TOXINS ))
A.NEUROLOGICAL 96%
Dysphagia Dysphonia
Dyspnea Diplopia
Dysarthria Dry mouth
Upper and lower extremities weakness
Blurred vision Fatigue
Dizziness Parasthesia
B.GASTROINTESTINAL:
Diarrhea Constipation
Nausea Vomiting
Abdominal cramps
C.MISCELLANEOUS:
Dizziness
Sore throat
Fatigue
5 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
Infant botulism. Infant botulism was first described in 1976. Unlike adults, infants younger than 12 months are vulnerable
to C. botulinum colonizing the intestine. Infants ingest spores in honey or simply by swallowing spore-containing dust or
dirt. The spores germinate in the large intestine and, once colonized, toxin is produced and absorbed into the infant's body
from the entire intestinal tract. The first symptoms include constipation, lethargy, and poor feeding. As infant botulism
progresses, sucking and swallowing (thus eating) become difficult. A nursing mother will often notice her own breast
engorgement as the first sign of her infant's illness. The baby suffers overall weakness and cannot control head
movements. Because of the flaccid paralysis of the muscles, the baby appears floppy. Breathing is impaired, and death
from respiratory failure is a very real danger.
Wound botulism. Confirmed cases of wound botulism have been linked to trauma such as severe crush injuries to the
extremities, surgery, and illegal drug use. Wound botulism occurs when Clostridia colonize an infected wound and
produce botulinum toxin. The symptoms usually appear four to 18 days after an injury occurs and are similar to food-
borne botulism, although gastrointestinal symptoms may be absent.
PHYSICAL FINDING:
Upper extremity weakness
Ptosis
Lower extremity weakness
Hypoactive gag reflex
Extraocular muscle weakness
6 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
Facial nerve dysfunction
Tongue weakness
Pupils fixed or dilated
Nystagmus and ataxia
Mental status--- alert 90% , lethargic , obtunded
Deep tendon reflexes –normal 50%, hypoactive or hyperactive.
Clue to diagnosis ( food borne ) :
1.Absence of fever
2.Normal mental status
3.Same neurological finding(( symmetrical ))
4.No sensory deficit
Clue to wound born:
1. 4—14 days of trauma
2. Fever related to infected wound
3. No GIT upsets
DIAGNOSIS:
Laboratory tests are used to make a definitive diagnosis, but if botulism seems likely, treatment starts immediately without
waiting for test results, which may take up to two days. Diagnostic tests focus on identifying the organism causing the
illness. This may involve performing a culture on contaminated material from the suspect food or the nose or throat of the
affected individual. In infant botulism, the infant's stool may be cultured to isolate the organism; this test may be
performed by the state health department or the Centers for Disease Control (CDC). Culture results are available from the
microbiology laboratory as soon as bacteria grow in a special plate incubated at temperatures at or above body
temperature. The growth of Clostridiumconfirms the diagnosis. Sometimes the organism cultured is not Clostridium as
suspected. The microbiology laboratory may use samples of the bacteria grown to perform other special techniques in
order to help identify the causative organism.
While waiting for diagnostic test results, doctors ask about recently consumed food, possible open sores, recent activities
and behavior, and other factors that may help to rule out other disease possibilities. A physical examination is done with
an emphasis on the nervous system and muscle function. As part of this examination, imaging studies such as CT and
MRI may be done and electrodiagnostic muscle function tests (electromyogram) or lumbar punctures may be ordered.
Laboratory tests look for the presence of botulinum toxin or Clostridia in suspected foods and/or the child's blood serum,
feces, or other specimens for traces of botulinum toxin or Clostridia. Magnesium levels may be measured, since
magnesium increases the activity ofClostridium. Additional diagnostic tests may be done to rule out other diseases or
conditions with similar symptoms.
Isolation of clostridium from infected person
Detection of the toxin
a. 10-50ml of serum ---- muose toxin neutralized test
b. 25-50gm of stool----- under aseptic technique
c. Gastric aspirate
d. Vomitus
Clostridium is not a normal flora of feces.
7 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL
Treatment:
First goal -- remove unabsorbed toxin from GIT
a.NGT for lavage
b.Enema with tap water
2
ND
GOAL=== adminster trivalent antitoxin (1vial I.M. / I.V.) REPEAT 4 HR to neutralize toxin
Drugs
Older children and adults with botulism are sometimes treated with an antitoxin derived from horse serum
that is distributed by the Centers for Disease Control and Prevention. The antitoxin (effective against toxin
types A, B, and E) inactivates only the botulinum toxin that is unattached to nerve endings. Early injection of
the antitoxin, ideally within 24 hours of onset of symptoms, can preserve nerve endings, prevent progression
of the disease, and reduce mortality.
Unfortunately, infants cannot receive the antitoxin used for adults. For them, human botulism immune
globulin (BIG) is the preferred treatment. It is available in the United States through the Infant Botulism
Treatment and Prevention Program in Berkeley, California. BIG neutralizes toxin types A, B, C, D, and E
before they can bind to nerves. This antitoxin can provide protection against A and B toxins for
approximately four months. Though many infants recover with supportive care, BIG cuts hospital stay in half
and, therefore, reduces hospital costs by 50 percent as well.
Aside from the specific antitoxin, no therapeutic drugs are used to treat botulism. Antibiotics are not
effective for preventing or treating botulism because the Clostridium group of toxins are not sensitive to
them. In fact, antibiotic use is discouraged for infants because bacteria could potentially release more toxin
into a baby's system as they are killed. Antibiotics can be used, however, to treat secondary respiratory tract
and other infections.
Surgery
Surgery may be necessary to clean an infected wound (debridement) and remove the source of the bacteria
producing the toxin. Antimicrobial therapy may be necessary.
3
RD
GOAL=== good nursing and supportive medical care.
Wound -------------- penicillin G 3X6 I.V.
DIFFERENTIAL DIAGNOSIS:
1. Mysthenia gravis--- repetitive stimulation of low and high ampilitude of nerve
2. Guillian - Barre syndrome
3. Cerebrovascular accident
4. C.O.POISONING
5. Tick paralysis
6. Poliomyelitis
7. Diphtheria
8. Lambert -Eaton syndrome
9. Shell fish poisoning
10. Drug reactions--- phenothiazine

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Botulism 2013 DR MAGDI SASI

  • 1. 1 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL BOTULISM Definition Botulism is an acute, progressive condition caused by botulinum toxin, a natural poison produced by the spore-forming bacteria Clostridium botulinum. Exposure to the botulinum toxin usually occurs from eating contaminated food although, in infants, it may be caused by specific types of clostridia obtained from soil or inhaled spores, causing growth of the bacteria in the infant's intestine. Botulinum toxin is a neurotoxin that blocks the ability of motor nerves to release acetylcholine, the neurotransmitter that relays nerve signals to muscles, a process that may result in unresponsive muscles, a condition known as flaccid paralysis. Breathing may be severely compromised in progressive botulism because of failure of the muscles that control the airway and breathing. Cause-Clostridium botulinum --------- Neurotoxin—acts on peripheral nervous system. It is a gram positive bacillus . Description Botulism occurs only rarely, but its high fatality rate makes it a great concern for those in the general public and in the medical community. Clinical descriptions of botulism reach as far back in history as ancient Rome andGreece. However, the relationship between contaminated food and botulism was not defined until the late 1700s. In 1793 the German physician, Justinius Kerner (1786–1862), deduced that a substance in spoiled sausages, which he called wurstgift (German for sausage poison), caused botulism. The toxin's origin and identity remained vague until Emile van Ermengem (1851–1932), a Belgian professor, isolated Clostridium botulinum in 1895 and identified it as the source of food poisoning . Three types of botulism have been identified: food-borne, wound, and infant botulism. The main difference between types hinges on the route of exposure to the toxin. Food-borne botulism accounts for 25 percent of all botulism cases and can usually be traced to eating contaminated home-preserved food. Infant botulism accounts for 72 percent of all cases. About 98 percent of infants recover with proper treatment. Although domestic food poisoning is a problem worldwide, concern is growing regarding the use of botulism toxin in biological warfare. At the end of the twentieth century 17 countries were known to be developing biological weapons, including the culture of botulism toxins.
  • 2. 2 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL Types ---1.Food borne 2.Infant 3.Wound borne 4.Undertermined Cause of death---- pulmonary copmplication Vital capacity is more sensitive indicator than ABG. A)Pneumonia B)Respiratory failure Physical factors of C.botulinum: The toxins---- heat liable ,destroyed 10—20 min in 80c The spores –germinate in: 1.An anerobic environment 2.Adequate water and nutrient 3.Low acidity ph 4.6 4.Tem less than 4c Source: 1.Wound 2.Food- improbably processed or stored and may be within normal taste. Transmission Botulism is not spread from one individual to another, but through exposure to the deadly botulinum toxin, a natural poison produced by certain Clostridium bacteria that may be found in preserved, especially canned, foods and sometimes in the intestines of infants. Botulism spores can cause widespread illness if introduced into the environment. Pathophysiology: Ingestion of the toxin in the food Absorption in small intestine Distributed by lymphatic and circulatory systems Reaches the peripheral nervous system and inhibit ACH release Bound to presynaptic membrane
  • 3. 3 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL Clinical features: When did the bacteria become pathogenic? Toxins produced by the bacterium Clostridium botulinum are the main culprit in botulism. Other members of the Clostridium genus can produce botulinum toxin, namely C. argentinense, C. butyricum, and C. baratii, but these are minor sources. To grow, these bacteria require a low-acid, oxygen-free environment that is warm (40–120°F or 4.4–48.8°C) and moist. Lacking these conditions, the bacteria transform themselves into spores that, like plant seeds, can remain dormant for years. Clostridia and their spores exist all over the world, especially in soil and aquatic sediments. They do not threaten human or animal health until the spores encounter an environment that favors growth. The spores then germinate, and the growing bacteria produce the deadly botulism toxin. How many toxins the bacteria have? Scientists have discovered that clostridia can produce at least seven types of botulism toxin, identified as A, B, C, D, E, F, and G. Humans are usually affected by A, B, E, and very rarely F; infants are affected by types A and B. Domesticated animals such as dogs, cattle, and mink are affected by botulism C toxin, which also affects birds and has caused massive die-offs in domestic bird flocks and wild waterfowl. Botulism D toxin can cause illness in cattle, and horses succumb to botulism A, B, and C toxin. There have been no confirmed cases of human or animal botulism linked to the G toxin.
  • 4. 4 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL Duration of onset of symptoms: After ingestion ---- 8 hours to 8 days The shorter the duration , the sever the symptoms. In humans, botulinum toxin latches onto specific proteins in nerve endings and irreversibly destroys them. These proteins control the release of acetylcholine, a neurotransmitter that stimulates muscle cells. With acetylcholine release blocked, nerves are not able to stimulate muscles. Ironically, this action of the botulinum toxin has given it a beneficial niche in the world of medicine. Certain medical disorders are characterized by involuntary and uncontrollable muscle contractions. Medical researchers have discovered that injecting a strictly controlled dose of botulinum toxin into affected muscles inhibits excessive muscle contractions. The muscle is partially paralyzed and normal movement is retained. ClinicalIy: Food-borne botulism. Food that has been improperly preserved or stored can harbor botulinum toxin-producing clostridia. Canned or jarred baby food has also been known to cause botulism. Symptoms of food-borne botulism typically appear within 18 to 36 hours of eating contaminated food, with extremes of four hours to eight days. Initial symptoms include blurred or double vision and difficulty swallowing and speaking. Possible gastrointestinal problems include constipation , nausea , and vomiting . As botulism progresses, the victim experiences weakness or paralysis, starting with the head muscles and progressing down the body. Breathing becomes increasingly difficult. Without medical care, respiratory failure and death are very likely. BOTULISM SHOULD BE SUSPECTED IN PATIENT WHO DEVELOP BILATERAL CRANIAL NERVE IMPAIRMENT WITH DESCENDING PARALYSIS OF THE LIMBS AND WEAKNESS. SYMPTOMS: (( A AND B TOXINS )) A.NEUROLOGICAL 96% Dysphagia Dysphonia Dyspnea Diplopia Dysarthria Dry mouth Upper and lower extremities weakness Blurred vision Fatigue Dizziness Parasthesia B.GASTROINTESTINAL: Diarrhea Constipation Nausea Vomiting Abdominal cramps C.MISCELLANEOUS: Dizziness Sore throat Fatigue
  • 5. 5 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL Infant botulism. Infant botulism was first described in 1976. Unlike adults, infants younger than 12 months are vulnerable to C. botulinum colonizing the intestine. Infants ingest spores in honey or simply by swallowing spore-containing dust or dirt. The spores germinate in the large intestine and, once colonized, toxin is produced and absorbed into the infant's body from the entire intestinal tract. The first symptoms include constipation, lethargy, and poor feeding. As infant botulism progresses, sucking and swallowing (thus eating) become difficult. A nursing mother will often notice her own breast engorgement as the first sign of her infant's illness. The baby suffers overall weakness and cannot control head movements. Because of the flaccid paralysis of the muscles, the baby appears floppy. Breathing is impaired, and death from respiratory failure is a very real danger. Wound botulism. Confirmed cases of wound botulism have been linked to trauma such as severe crush injuries to the extremities, surgery, and illegal drug use. Wound botulism occurs when Clostridia colonize an infected wound and produce botulinum toxin. The symptoms usually appear four to 18 days after an injury occurs and are similar to food- borne botulism, although gastrointestinal symptoms may be absent. PHYSICAL FINDING: Upper extremity weakness Ptosis Lower extremity weakness Hypoactive gag reflex Extraocular muscle weakness
  • 6. 6 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL Facial nerve dysfunction Tongue weakness Pupils fixed or dilated Nystagmus and ataxia Mental status--- alert 90% , lethargic , obtunded Deep tendon reflexes –normal 50%, hypoactive or hyperactive. Clue to diagnosis ( food borne ) : 1.Absence of fever 2.Normal mental status 3.Same neurological finding(( symmetrical )) 4.No sensory deficit Clue to wound born: 1. 4—14 days of trauma 2. Fever related to infected wound 3. No GIT upsets DIAGNOSIS: Laboratory tests are used to make a definitive diagnosis, but if botulism seems likely, treatment starts immediately without waiting for test results, which may take up to two days. Diagnostic tests focus on identifying the organism causing the illness. This may involve performing a culture on contaminated material from the suspect food or the nose or throat of the affected individual. In infant botulism, the infant's stool may be cultured to isolate the organism; this test may be performed by the state health department or the Centers for Disease Control (CDC). Culture results are available from the microbiology laboratory as soon as bacteria grow in a special plate incubated at temperatures at or above body temperature. The growth of Clostridiumconfirms the diagnosis. Sometimes the organism cultured is not Clostridium as suspected. The microbiology laboratory may use samples of the bacteria grown to perform other special techniques in order to help identify the causative organism. While waiting for diagnostic test results, doctors ask about recently consumed food, possible open sores, recent activities and behavior, and other factors that may help to rule out other disease possibilities. A physical examination is done with an emphasis on the nervous system and muscle function. As part of this examination, imaging studies such as CT and MRI may be done and electrodiagnostic muscle function tests (electromyogram) or lumbar punctures may be ordered. Laboratory tests look for the presence of botulinum toxin or Clostridia in suspected foods and/or the child's blood serum, feces, or other specimens for traces of botulinum toxin or Clostridia. Magnesium levels may be measured, since magnesium increases the activity ofClostridium. Additional diagnostic tests may be done to rule out other diseases or conditions with similar symptoms. Isolation of clostridium from infected person Detection of the toxin a. 10-50ml of serum ---- muose toxin neutralized test b. 25-50gm of stool----- under aseptic technique c. Gastric aspirate d. Vomitus Clostridium is not a normal flora of feces.
  • 7. 7 DR MAGDI AWAD SASI 2013 INFECTION RARE BUT IF MISSED FATAL Treatment: First goal -- remove unabsorbed toxin from GIT a.NGT for lavage b.Enema with tap water 2 ND GOAL=== adminster trivalent antitoxin (1vial I.M. / I.V.) REPEAT 4 HR to neutralize toxin Drugs Older children and adults with botulism are sometimes treated with an antitoxin derived from horse serum that is distributed by the Centers for Disease Control and Prevention. The antitoxin (effective against toxin types A, B, and E) inactivates only the botulinum toxin that is unattached to nerve endings. Early injection of the antitoxin, ideally within 24 hours of onset of symptoms, can preserve nerve endings, prevent progression of the disease, and reduce mortality. Unfortunately, infants cannot receive the antitoxin used for adults. For them, human botulism immune globulin (BIG) is the preferred treatment. It is available in the United States through the Infant Botulism Treatment and Prevention Program in Berkeley, California. BIG neutralizes toxin types A, B, C, D, and E before they can bind to nerves. This antitoxin can provide protection against A and B toxins for approximately four months. Though many infants recover with supportive care, BIG cuts hospital stay in half and, therefore, reduces hospital costs by 50 percent as well. Aside from the specific antitoxin, no therapeutic drugs are used to treat botulism. Antibiotics are not effective for preventing or treating botulism because the Clostridium group of toxins are not sensitive to them. In fact, antibiotic use is discouraged for infants because bacteria could potentially release more toxin into a baby's system as they are killed. Antibiotics can be used, however, to treat secondary respiratory tract and other infections. Surgery Surgery may be necessary to clean an infected wound (debridement) and remove the source of the bacteria producing the toxin. Antimicrobial therapy may be necessary. 3 RD GOAL=== good nursing and supportive medical care. Wound -------------- penicillin G 3X6 I.V. DIFFERENTIAL DIAGNOSIS: 1. Mysthenia gravis--- repetitive stimulation of low and high ampilitude of nerve 2. Guillian - Barre syndrome 3. Cerebrovascular accident 4. C.O.POISONING 5. Tick paralysis 6. Poliomyelitis 7. Diphtheria 8. Lambert -Eaton syndrome 9. Shell fish poisoning 10. Drug reactions--- phenothiazine