Physiology B – Oral revalida  difficulty in swallowing and speaking

Case 2 – BOTULISM  Vomiting, diarrhea, constipation and abdominal swelling

1F2 - Group 8
CASE OUTLINE
I. Background of the Disease
II. Case Summary
III. Related Physiology Principles
IV. Pathophysiology of the Case
V. Treatment
BACKGROUND OF THE DISEASE
BOTULISM
- a rare but life-threatening condition caused by toxins from the
bacteria called Clostridium botulinum.
- mainly a foodborne intoxication, but can also be caused by intestinal
infection with C. botulinum in infants, wound infections, and by
inhalation.
- may refer to foodborne botulism, infant botulism, wound botulism, and
inhalation botulism or other types of intoxication.
- General complications: it affects muscle control throughout your
body which may manifest the ff.:
 Flaccid paralysis
 Difficulty speaking
 Trouble swallowing
 Long-lasting weakness
 Shortness of breath
 most immediate danger and most common cause of death in
botulism: respiratory paralysis (not be able to breathe)
Clostridium botulinum
- is a gram-positive (anaerobic) bacterium that produces dangerous
toxins (botulinum toxins) under low-oxygen conditions.
- produces spores which are heat-resistant and exist widely in the
environment (inc. soil, river and sea water); these germinate, grow
and excrete toxins in the absence of oxygen.
- will not grow in acidic conditions: pH<4.6; thus, toxin will not be
formed in acidic foods (however, a low pH will not degrade any pre-
formed toxin)
- Combinations of low storage temperature and salt contents and/or pH
are also used to prevent the growth of the bacteria or the formation of
the toxin.
Botulinum toxins
- are very lethal neurotoxic substances that block nerve functions which
may lead to respiratory and muscular paralysis.
- prevents the release of the neurotransmitter acetylcholine from axon
endings at the neuromuscular junction and thus causes flaccid
paralysis (muscle contraction is weakened or lost).
- 7 distinct forms of botulinum toxin: types A to G; all of which block the
release of acetylcholine from nerve endings – inducing muscle
weakness
 Types A, B, E, and rarely F - cause human botulism
 Types C, D and E cause illness in other mammals, birds and fish.
- found in a variety of foods, including low-acid preserved vegetables,
such as green beans, spinach, mushrooms, and beets; fish, including
canned tuna, fermented, salted and smoked fish; and meat products,
such as ham and sausage.
TYPES OF EXPOSURE TO BOTULINUM NEUROTOXIN
Foodborne botulism
- caused by ingestion of potent neurotoxins (botulinum toxins), formed
in contaminated foods (commonly from homemade canned,
preserved or fermented foodstuffs).
- Manifestations:
(early symptoms)
 descending, flaccid paralysis (can cause respiratory failure)
 marked fatigue
 weakness
 vertigo (usually followed by blurred vision)
 dry mouth
(progressed symptoms)
 weakness in the neck and arms
 after which the respiratory muscles and muscles of the lower
body are affected.
- Symptoms usually appear within 12 to 36 hours (within a minimum
and maximum range of 4 hours to 8 days) after exposure.
Infant botulism
- occurs when infants (mostly under 6 months of age) ingest C.
botulinum spores, which germinate into bacteria that colonize in the
gut and release toxins.
- Manifestations:
 constipation (often the first sign)
 loss of appetite
 weakness
 an altered cry
 a striking loss of head control
- most common source is spore-contaminated honey
- In most adults and children older than about 6 months, natural
defenses in intestines that develop over time prevent germination and
growth of the bacterium.
Wound botulism
- Rare; occurs when the spores get into an open wound and are able to
reproduce in an anaerobic environment.
- Symptoms are similar to foodborne botulism.
- has been associated with substance abuse, particularly when
injecting black tar heroin.
Inhalation botulism
- Rare; does not occur naturally;
- it is associated with accidental or intentional events (such as
bioterrorism) which result in release of the toxins in aerosols.
- exhibits a similar clinical footprint to foodborne botulism.
- Median lethal dose for humans: estimated at 2 nanograms of
botulinum toxin per kilogram of bodyweight (approximately 3 times
greater than in foodborne cases).
- Symptoms proceed in a similar manner to ingestion of botulinum toxin
and culminate in muscular paralysis and respiratory failure.
Other types of intoxication
 Waterborne botulism - could theoretically result from the ingestion
of the pre-formed toxin.
 Botulism of undetermined origin usually involves adult cases where
no food or wound source can be identified; comparable to infant
botulism and may occur when the normal gut flora has been altered
as a result of surgical procedures or antibiotic therapy.
 Botox - a pharmaceutical product predominantly injected for clinical
and cosmetic use; it is produced from the bacteria Clostridium
botulinum; employ the purified and heavily diluted botulinum
neurotoxin type A.
CASE SUMMARY
MEDICAL HISTORY:
- Two days prior to illness, patient consumed food from a reputable
commercial food store and from an artisanal producer.
o Botulinum toxin can be acquired from improperly canned food and
home-prepared foods.
CLINICAL FINDINGS:
● Abdominal pain and nausea
- Irritation of the Gl tract due to contaminated food.
● Constipation, Tympanitic abdomen with hypoactive bowel
Sounds
- Decrease motility of the Gl tract due to inhibition of Ach release.
● Difficulty in swallowing and breathing
- Decreased vital capacity and increased residual volume is due to
inability to overcome recoil of chest wall outward and respiratory
muscle weakness resulted from inhibition of Ach release by the
botulinum toxin reducing respiratory muscle contraction which will
eventually lead to: Respiratory Failure

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 ● Acute Flaccid Paralysis
- Reduced or absence of voluntary muscle contraction that
resulted from incapability of Ach to bind to nicotinic 1 receptor
(NMJ) due to blockage of Ach release at the presynaptic cleft
by the botulinum toxin.
● +1 DTR (Deep Tendon Reflex) both sides of upper and lower
extremities
- means that the there is presence but depressed deep tendon
reflex which indicates disease or injury of the lower motor
neuron.
● Sensory is 100% For both sides
- Absence of sensory findings rules out Guillain – Barre
Syndrome
RELATED PHYSIOLOGY PRINCIPLES
NERVE & ELECTROPHYSIOLOGY
Signal Transmission at Synapse:
 The Soma (specifically in the Golgi Apparatus) of the neuron produces
empty vesicles and transports it to the axon terminals;
 Neurotransmitters (NTAs) like Acetylcholine (Ach) are produced (in
the cytosol) of the axon terminal (pre-synaptic) and are stored in these
vesicles.
I. Action potential from the cell body goes to the pre-synaptic area
causing a depolarizing change.
II. Voltage gated Ca++ channels open causing Ca++ Influx.
III. Ca++ will bind with and bring the vesicle to the pre-synaptic
membrane;
IV. This Ca++ will be sensed by the SNARE protein,
SYNAPTOTAGMIN (Calcium-sensor), which will be activated to
help Ca++ in the effective movement of the vesicle to the
presynaptic membrane.
V. When the vesicle is near the membrane, there will be an activation
of the ff. SNAREs:
 SYNAPTOBREVIN – a Vesicle Associated Membrane Protein
(VAMP), which is attached to the vesicle (hence, the name);
 SYNTAXIN and SNAP25 – called t-SNAREs, which is
attached to the pre-synaptic membrane.
- Upon activation, Synaptobrevin will immediately fuse with Syntaxin,
and this is enhanced by SNAP25. The fusion serves as a bridge to
allow easy release of the NTAs in the vesicles towards the
Synaptic cleft via exocytosis.
RECALL:
SNARE Proteins: are necessary for normal release of NTAs stored
in the vesicle towards the synaptic cleft; important for the
communication of the pre and post synaptic
V-SNAREs: associated with the vesicle
 Synaptotagmin
 Synaptobrevin
T-SNAREs: attached to the membrane of the pre-synaptic cell
 Syntaxin
 SNAP25
MUSCLE PHYSIOLOGY
At the Neuromuscular Junction (NMJ)
Recall:
 NMJ – is a synapse between a muscle tissue and motor nerve.
 Sarcolemma – plasma membrane of muscles (m.)
 Sarcoplasm – cytoplasm of m.
 Sarcoplasmic reticulum – Smooth Endoplasmic Reticulum of m.
 Transverse or t-tubule – invagination of the sarcolemma
 End-plate potential – local potential of skeletal muscles
I. The NTAs released in the synaptic cleft, in this
case Ach, bind to Nicotinic 1 (N1 or NM)
receptors (ionotropic) found at the apex in the end-plate (post-
synaptic terminal of skeletal muscle).
II. Upon binding of Ach to N1, Cation channels of the sarcolemma
will open, causing influx or efflux of Cations (Positive ions).
 Influx: Ca+, Na+ (more influx)
 Efflux: K+, Mg+
III. The influx from Cations is greater, causing an end-plate potential,
the sarcolemma’s RMP will become less negative to positive –
opening the Voltage-gated Na+ channels
IV. Na+ influx from the Voltage-gated Na+ Channels will generate an
action potential in the sarcolemma.
V. Action Potential travels down the T-tubules to release the Ca++ for
contraction (excitation-contraction coupling)
Excitation-Contraction Coupling:
VI. When the action potential
reaches the T-tubules, the
voltage-gated Dihydropyridine
receptor will open in the inside
touching the mechanically-
gated calcium receptor called
Ryanodine receptor
VII. Ryanodine receptor (located
in the cisterns) will open to
release Ca++ from the
Sarcoplasmic Reticulum into
the sarcoplasm
VIII. Ca++ will bind to Troponin C; troponin C facilitates movement of
the associated tropomyosin molecule towards cleft of actin
filament. The movement exposes myosin binding site on the
actin filament and allows cross bridge.
IX. Once myosin and actin have bound, ATP-dependent
conformational change in myosin results in movement of the actin
filament towards the center. (Sliding Filament Theory)
- Power stroke for pulling actin is a result of the bond between
the head and the actin which causes a conformational change
in the head causing it to tilt toward the arm of the cross bridge.
X. The ATP comes near the myosin ATPase; ATP is hydrolyzed;
myosin will perform the power stroke then will release ADP and Pi.
XI. After a fraction of a second, the calcium ions are pumped back into
the sarcoplasmic reticulum by a Ca++ membrane ATPase-pump
(SERCA1) and remain stored in the reticulum until a new muscle
action potential comes along; this removal of calcium ions from the
myofibrils causes the muscle contraction to cease.
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 Recall:
 Dihydropyridin (DHP)
- Voltage gated receptor
- Found in the t-tubule
- Stimulates Ryanodine Receptors
 Ryanodine Receptors
- Mechanically gated
- Found in the Sarcoplasmic Reticulum
- When opened, it stimulates the calcium to release and bind the
Troponin-C
 Transverse Tubules
- Internal extension of the sarcolemma
- Ratio of the T-tubule to Sarcoplasmic Reticulum = 2:1
 Calsequestrin
- Special protein that has a high affinity to calcium that makes the
calcium stay inside the Sarcoplasmic Reticulum until another AP
stimulates.
PATHOPHYSIOLOGY OF THE CASE
Botulinum toxin
1. The toxin has a heavy chain and a light chain
2. The heavy chain binds to proteins on the surface of the axon
terminals.
3. The toxin enters the cells via endocytosis.
4. The disulfide bond between the Light chain and Heavy chain is
cleaved;
5. The toxin’s light chain is released from the vesicle into the cytoplasm
of the presynaptic terminal via a channel formed by the heavy chain.
6. The light chain cleaves the integral proteins of the SNARE complex,
preventing the docking of the vesicle containing acetylcholine to the
plasma membrane
7. Acetylcholine will not be released in the synaptic cleft
8. There will be no formation of acetylcholine-receptor complex
9. No muscle contraction (Flaccid paralysis)
- The toxin requires 24-72 hours to take effect, reflecting the time
necessary to disrupt the synaptosomal process. In very rare
circumstances, some individuals may require as many as five days for
the full effect to be observed. Peaking at about 10 days, the effect of
botulinum toxin lasts nearly 8-12 weeks (Nigam & Nigam, 2010).
Figure 1. Mechanism of Action of Botulinum Toxin (Arnon et al., 2001)
TREATMENT
ANTITOXIN
- Effective antitoxin therapy can be achieved when it is administered to
patients within 24 h of patients exhibiting neurologic signs of botulism.
The neutralizing antibodies prevent further progression of paralysis by
binding to the toxin itself, thereby preventing it from binding to
presynaptic membrane receptors. This timely administration of antitoxin
therefore minimizes the severity of the disease.
- Currently, there are two FDA-approved antitoxin products available: (i)
the bivalent botulinum equine antitoxin (BoNT/A and BoNT/B; CDC);
and (ii) the human botulism immune globulin for adults and infants,
respectively (Ramasamy et al., 2010).
ANTIBIOTICS (Wound botulism)
- The use of local antibiotics such as penicillin G or metronidazole may
be helpful in eradicating Clostridium botulinum in wound metabolism.
Penicillin G interferes with synthesis of cell wall mucopeptide during
active multiplication, resulting in bactericidal activity against susceptible
microorganisms. Antibiotic use is not recommended for infant botulism
because cell death and lysis may result in the release of more toxin.
BREATHING ASSISTANCE
- For patients having trouble breathing, a mechanical ventilator is
necessary for as long as several weeks as the effects of the toxin
gradually lessen. The ventilator forces air into the patient’s lungs
through a tube inserted in the airway through the nose or mouth.
REHABILITATION
- As the patient’s recover, they may also need therapy to improve
speech, swallowing and other functions affected by the disease.
References:
- Arnon S.S., Schechter R., Inglesby T.V., Henderson D.A., Bartlett J.G.,
Ascher M.S., et al. (2001). Botulinum Toxin as a Biological Weapon:
Medical and Public Health Management [Electronic version]. JAMA,
285(8), 1059-1070.
- Nigam, P. K., & Nigam, A. (2010). Botulinum toxin. Indian journal of
dermatology, 55(1), 8-14.
- Ramasamy, S., Liu, C. Q., Tran, H., Gubala, A., Gauci, P., McAllister,
J., & Vo, T. (2010). Principles of antidote pharmacology: an update on
prophylaxis, post-exposure treatment recommendations and research
initiatives for biological agents. British journal of pharmacology, 161(4),
721-48.
- https://www.who.int/news-room/fact-sheets/detail/botulism
- https://www.mayoclinic.org/diseases-conditions/botulism/symptoms-
causes/syc-20370262?p=1
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