Professor Soltanzadeh

پروفسور محمد حسین سلطان زاده

      استاد دانشگاه علوم پزشکی شهید بهشتی
     متخصص کودکان ونوزادان
        طی دوره بالینی عفونی از میوکلینیک آمریکا
دبیر برگزاری کنفرانس های ماهیانه گروه اطفال
دانشگاه علوم پزشکی شهید بهشتی

دکتر زهرا پور نصیر
فوق تخصص کلیه اطفال
به اتفاق اعضای هیئت علمی گروه کودکان بیمارستان لقمان حکیم

تشخیص

Infant Botulism

Infant botulism was first recognized and described in 1976.
it has become the most commonly reported syndrome caused by botulinum toxin.
Over 60% of newly reported botulism cases are infantile, accounting for approximately 60 -110 cases per year in the United States.

Botulism typically results from toxins produced by the anaerobic, spore forming gram-positive bacilli Clostridium botulinum.
the genetically and phenotypically distinct clostridial species botulinum, baratii, and butyricum are all recognized as causative agents of infant botulism.

Clostridia produce eight botulinum neurotoxins designated A-G, but only botulinum toxin types A, B, E, and F cause disease in humans. Type C and D cause disease in animals, and type G has been isolated from soil but is not associated with any known illness. The vast majority of cases of infant botulism are caused by botulinum toxin types A and B.

The Botulinum serotypes cause the neuroparalytic syndromes by a mechanism of blocking neurotransmitter release.
It is presynaptic blockade (Inhibition of acetylcholine release )

The individual botulinum serotypes cause neuromuscular paralysis of significantly different durations. Recent pharmacokinetic studies of botulinum neurotoxins used therapeutically suggest that neuromuscular recovery from types E and F may occur more quickly than from types A and B.

The toxins, which block cholinergic synapses, cause four recognized types of distinct human disease, including:
- Food-borne botulism
- Wound botulism
- Adult intestinal colonization
- Infant botulism.

Foodborne botulism occurs through ingestion of preformed toxin, whereas in the other three types, disease occurs through the infection and growth of clostridial organisms that germinate in a wound or in the gastrointestinal tract and then produce the toxins, which are absorbed into the body.

Infant botulism usually occurs between 2 weeks and 1 year of age, with a median age of 10 weeks.
Botulism in infants younger than 2 weeks rarely is reported, the youngest patient in the literature was 6 days of age when he became ill, and one infant with confirmed botulism in California was only 54 hours old at the onset of symptoms.
Hypothesized incubation period for botulism is 3-30 days (the California infant with symptoms after 54 hours of life suggests that this time period may be shorter for infection with some strains of clostridia).

Clinically, cholinergic blockade in infant botulism causes symptoms ranging from mild hypotonia to severe, flaccid paralysis and absence of cranial nerve reflexes.
The differential diagnosis of infant botulism includes common causes of hypotonia in an infant

Differential diagnosis of infantile botulism
Bacterial sepsis/meningitis
Electrolyte disturbance (hypocalcemia, hypernatremia, etc.)
Inborn errors of metabolism
Poliomyelitis
Guillain-Barré syndrome
Congenital myasthenia gravis
Poisoning (Organophosphate, Heavy metal,…)

Constipation is often one of the first signs of botulism infection. Other early signs include a weak cry, decreased spontaneous movement, hypotonia, and inadequate performance of major motor developmental milestones.

Blockade of cholinergic synapses affects the autonomic nervous system as well as the neuromuscular junction, causing a symmetric, descending motor weakness and flaccid paralysis with autonomic dysfunction progressing over the course of hours to a few days, proceeding from cranial nerves to the trunk, extremities, and finally the diaphragm.

On physical examination:
an infant with botulism is usually afebrile with normal skin color. Both autonomic and motor response to stimulation may be decreased along with decreased spontaneous movement. Cranial nerve palsies may be found with sluggishly reactive or fixed pupils, and diminished or absent corneal, gag, and oculovestibular reflexes. Deep tendon reflexes may be either diminished or intact.

The clinical course of infant botulism tends to be slowly progressive followed by a long recovery period, and return of autonomic function may be slower than neuromuscular function.

Environmental exposures such as living in a rural area or a having a parent who works with soil, have been identified as important risk factors for infant botulism. (Spores from all botulinum organisms are present in samples of dust and soil.)
Consumption of honey can be another source of spores.
Because of a successful public awareness campaign, infant botulism linked to honey has been decreasing in the United States and is now associated with only 20% of cases, compared with 59% of cases in Europe.
Hospital exposures have also been postulated in case reports of early infant botulism, but likely result from soil or dust disturbances rather than nosocomial transmission of clostridia.

Outside of the United States, infant botulism is more rare and tends to occur in countries where food-borne botulism is also found.
Contaminated honey is found throughout the world, with up to 6-10% of samples containing Clostridium botulinum spores.

Diagnosis:
Electrophysiology is usually the quickest way to make a diagnosis of botulism. The electrodiagnostic findings usually include normal nerve conduction studies. Electromyography commonly reveals increased insertional activity along with polyphasic motor units of small amplitude and short duration, consistent with acute denervation, although these finding are not specific for botulism and can be seen in axonal neuropathies or certain myopathies. Typically, M-wave amplitude is small, and paired nerve stimuli at short intervals or rapid repetitive nerve stimulation cause an incremental response, whereas paired nerve stimuli at long intervals or slow repetitive nerve stimulation may cause a decremental response. Cases of botulism with mild to moderate weakness have increased jitter and blocking on single-fiber electromyography. However, variable results have been reported, and in severe botulism findings can be relatively nonspecific.

Diagnosis:
Other diagnostic tests, including blood, urine and cerebrospinal fluid analysis and culture, metabolic and hepatic profiles, are generally within normal limits. No improvement with an edrophonium challenge helps to exclude myasthenia gravis. Electroencephalography and neuroimaging should also be within normal limits if no hypoxic event has occurred as the syndrome progresses.

Diagnosis:
Laboratory identification of botulinum toxins or organisms in the stool or serum confirms the diagnosis of infant botulism.
The mouse bioassay is considered the most sensitive technique for diagnosis, but the results may take several days.

Diagnosis:
For optimal laboratory testing, normally passed stool should be collected. However, stool samples are often difficult to collect because of constipation related to the cholinergic blockade, and an enema with sterile water may be required for adequate (at least 25 mL) sample collection.
Serum is much less helpful because serum testing has a low sensitivity compared with stool testing, but may be sent in suspected cases if stool collection is difficult. While a positive serum test may help, a negative serum test does not exclude the possibility of infant botulism.
All specimens should be collected sterilely, refrigerated, and shipped to qualified laboratories in insulated containers with cold packs.
Stool samples should continue to be collected until the diagnosis is clear.

Treatment:
treatment for infantile botulism was largely supportive, consisting of respiratory and nutritional care.
However, a significant advancement in treatment came in October 2003, when human botulism immune globulin (Baby-BIG) was approved by the Food and Drug Administration for use in infant botulism.

Treatment:
Baby-BIG is derived from pooled plasma of adults immunized with pentavalent botulinum toxoid and selected for high titers of neutralizing antibodies against type A and B toxin. The activity of this product against toxin types C-F is unknown.
The most common adverse effect was an erythematous rash..

Treatment:
Trivalent equine immunoglobulin to toxin types A, B, and E is the currently available antitoxin for botulism in adults, but is not recommended for infant botulism even if Baby-BIG is unavailable.
This recommendation is based on the high rate of hypersensitivity reactions and the short half-life (5-8 days) of the antitoxin, which is considered inadequate for a syndrome caused by ongoing intestinal absorption of botulinum toxin.

Treatment:
Although infants with botulism are usually afebrile, initial treatment often includes antibiotics for presumed sepsis. However, treatment with aminoglycosides, which have neuromuscular blocking activity, may potentiate or exacerbate the botulinum neuromuscular blockade.

Prognosis:
The prognosis for full recovery from infant botulism without residual weakness is generally good if no complications occur.
However, aspiration from decreased gastric emptying and death from paralysis of the diaphragm can occur quickly.
In hospitalized patients, mortality rates are reported to be from 3% to 5%. Complications may also result from prolonged intubation and mechanical ventilation.
Nutritional support with nasogastric enteral feeds should be started as soon as the diagnosis is made, anticipating the possibility of a prolonged course.

	Approach to a Hypotonic Infant
	The maintenance of normal tone requires intact central and peripheral nervous systems. Hypotonia is a common symptom of neurological dysfunction and occurs in diseases of the brain, spinal cord, nerves, and muscles . One anterior horn cell and all the muscle fibers that it innervates compose a motor unit. The motor unit is the unit of force. Weakness is a symptom of all motor unit disorders. A primary disorder of the anterior horn cell body is a neuronopathy, a primary disorder of the axon or its myelin covering is a neuropathy, and a primary disorder of the muscle fiber is a myopathy.
	Approach to Diagnosis The first step in diagnosis is to determine whether the disease location is in the brain, spine, or motor unit. More than one site may be involved .
	The brain and the peripheral nerves are concomitantly involved in some lysosomal and mitochondrial disorders. Brain and skeletal muscles are abnormal in infants with acid maltase deficiency and neonatal myotonic dystrophy. Newborns with severe hypoxic-ischemic encephalopathy may have hypoxic injury to the spinal cord and the brain. Several motor unit disorders produce sufficient hypotonia at birth to impair respiration and cause perinatal asphyxia .Such infants may have cerebral hypotonia as well. Newborns with spinal cord injuries are frequently the product of long, difficult deliveries in which brachial plexus injuries and hypoxic-ischemic encephalopathy are concomitant problems.
	Combined Cerebral and Motor Unit Hypotonia Acid maltase deficiency Familial dysautonomia Giant axonal neuropathy Hypoxic-ischemic encephalomyopathy Infantile neuronal degeneration Lipid storage diseases Mitochondrial (respiratory chain) disorders Neonatal myotonic dystrophy Perinatal asphyxia secondary to motor unit disease
	The term cerebral hypotonia encompasses all causes of postural hypotonia caused by a cerebral disease or defect. Clues to the Diagnosis of Cerebral Hypotonia Cerebral hypotonia in newborns usually does not pose diagnostic difficulty. The history and physical examination identify the problem. Many clues to the diagnosis of cerebral hypotonia exist . Most important is the presence of other abnormal brain functions, including decreased consciousness and seizures. Cerebral malformation is the likely explanation for hypotonia in an infant with dysmorphic features or with malformations in other organs.
	Clues to Cerebral Hypotonia Abnormalities of other brain functions Dysmorphic features Fisting of the hands Malformations of other organs Movement through postural reflexes Normal or brisk tendon reflexes Scissoring on vertical suspension
	Clues to Motor Unit Disorders Disorders of the motor unit are not associated with malformations of other organs except for joint deformities and the maldevelopment of bone structures. The face sometimes looks dysmorphic when facial muscles are weak or when the jaw is underdeveloped. Tendon reflexes are absent or depressed. Loss of tendon reflexes that is out of proportion to weakness more likely is caused by neuropathy than myopathy, whereas diminished reflexes that are consistent with the degree of weakness more often are caused by myopathy than neuropathy). Muscle atrophy suggests motor unit disease but does not exclude the possibility of cerebral hypotonia. Failure of growth and atrophy can be considerable in brain-damaged infants. The combination of atrophy and fasciculations is strong evidence of denervation. The observation of fasciculations in newborns and infants is often restricted to the tongue, however, and distinguishing fasciculations from normal random movements of an infant’s tongue is difficult unless atrophy is present.
	Clues to Motor Unit Disorders Absent or depressed tendon reflexes Failure of movement on postural reflexes Fasciculations Muscle atrophy No abnormalities of other organs
	Summary of types of hypotonia Central hypotonia Site of lesion: Brain, brainstem, spinal cord (above the origin of the cranial nerve nuclei or anterior horn cells). Causes: Brain malformations, chromosomal aberration: e.g. Down’s syndrome, Prader-Willi syndrome, cerebellar hypoplasia (see Figs 1–3). Clues to diagnosis: History of brain insult, seizures, dysmorphic features, lack of interest in surroundings, abnormal head size, Normal spontaneous movements, normal or increased reflexes, persistence of primitive reflexes, organomegaly.
	Peripheral hypotonia Site of lesion: Cranial nerve nuclei, anterior horn cell, nerve roots, peripheral nerves, neuromuscular junction or muscle. Causes: Spinal cord injury, spinal muscular atrophy, poliomyelitis, peripheral neuropathy, Guillain-Barre syndrome, myasthenia gravis, infantile botulism, congenital or metabolic myopathy, muscular dystrophy. Clues to diagnosis: Decreased fetal movements, alertness and responsiveness, weakness with little spontaneous movements, absent or decreased reflexes, fasciculations, muscle atrophy, and sensory loss.
	Mixed hypotonia Features of both central and peripheral hypotonia due to combined central and peripheral pathology (e.g. peroxisomal, lysosomal, and mitochondrial disorders, or any cause of peripheral hypotonia with an acquired hypoxic ischemic brain insult)