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The Gorgas Course in Clinical Tropical Medicine has moved this week to Iquitos, on the banks of the Amazon River.  Iquitos, with a population of approximately 500,000, is the largest city in the world that is reachable only by air and by river.  The nearest road ends over 400 km away.

The following patient was seen by Gorgas Course participants in the Intensive Care Unit of the 200-bed Hospital de Iquitos.

History:  37 yo male admitted with a 4-day history of difficulty in opening the mouth and difficulty in swallowing, as well as stiffness and spasm in anterior and posterior neck muscles.  This progressed to painful episodic generalized muscle rigidity in the limbs and abdomen.  By the time of admission the patient was drooling and no longer able to control his salivary secretions.  He had suffered trauma to the right arm about 3 weeks prior to admission.  No relevant past medical history.  No suspicious dietary ingestions, no animal bites, and no exposure to anyone that was ill.

Epidemiology:  Lifelong resident of Iquitos.  He does not remember his vaccination history.

Physical Examination:  Afebrile, BP 127/90, pulse 88, respirations 24.  Diaphoretic [Image A].  Trismus exaggerated during periods of spasm [Image B], very limited mouth opening, contraction of paracervical and neck muscles [Image C], and paravertebral muscle spasm with arching of the back [Image D] were present as were generalized spasmodic muscle contractions.  Sensory examination normal.

Laboratory Examination:  No hematologic or biochemical abnormalities.

Discussion:  Generalized tetanus is a purely clinical diagnosis with highly characteristic features, and, as in this case, the diagnosis is usually made within minutes of arrival at a medical facility.  In general, disease begins with trismus or lockjaw, which are spasms of the masseter muscles, although, initial symptoms may occur in other muscle groups.  After a variable period the symptoms progress to generalized muscular rigidity, on which is superimposed increasingly severe generalized reflex muscular spasms manifested by the characteristic sardonic smile (risus sardonicus), opisthotonos (arched back), and spasm of respiratory muscles and larynx.  In severe cases there are prolonged spasms occurring less than 1 hour apart, and in very severe cases there is autonomic hyperactivity with sweating, fever, tachycardia, salivation, arrhythmias, hyper- or hypotension, hyperthermia, etc.  Some aspects of generalized disease can be mimicked by hypocalcemic tetany, phenothiazine induced dystonia, epilepsy, rabies, strychnine poisoning, or narcotic withdrawal, but the history of wound [Image E for this patient] (not always elicited), epidemiology, and clinical course of tetanus usually lead to little confusion.  Mild localized tetanus in which trismus does not progress to generalized disease with reflex spasms is rare.  In the initial phase, the trismus itself has a broader differential diagnosis including dipththeria, partotitis, retropharyngeal abscess, and traumatic injury.

Disease is caused by a toxin, tetanospasmin, released by Clostridium tetani which infect the wound.  Spread of toxin is both retrograde through the affected axons as well as via blood to nerve endings in other parts of the body.  Masseters are usually affected first due to their short axons.  The action is pre-synaptic, irreversible, and blocks inhibitory neurotransmitter action leading to muscle spasm.  Poor prognostic indicators include short incubation period (< 7 days) from time of the wound to onset of symptoms (4 days here), short period of onset (< 48 hours), from onset of symptoms to first reflex spasm (3 days here), and high-risk portal of entry (compound fracture, gynecologic, postoperative, and burns).

Management is complex and must be done in a well-equipped Intensive Care Unit (ICU).  Non-ICU care is associated with almost universal mortality.  General principles are listed here, but detailed written dosing protocols must be available and used for most interventions.

1. Airway – in severe generalized tetanus, immediate endotracheal intubation to protect against laryngeal spasm is indicated and our patient was rapidly intubated on arrival due to his difficulty controlling salivary secretions.  For those with poor prognostic signs, where even survivors will require weeks of intensive care while synapses regenerate, immediate or early tracheostomy is advised.
2. Relaxation-Sedation – must be titrated to eliminate reflex spasm.  Large amounts of diazepam, up to 20 mg/kg/day by IV bolus; midazolam is increasingly used.  Patients are relatively refractory to the sedating and respiratory depressive effects of diazepam.  Chlorpromazine can be used to augment the effect of diazepam.  If this regimen does not control spasm, as occurred in this case, artificial ventilation and complete neuromuscular blockade with vecuronium as the drug of choice is indicated.
3. Neutralize toxin – either human hyperimmune globulin (ideal) or equine anti-tetanus globulin (preceded by an intradermal test dose) should be given intramuscularly.  Our patient was awaiting arrival of intramuscular equine immunoglobulin at the time of examination.  As is the case in many developing countries, human IG is not available in Iquitos.  Some centers give a portion of the globulin intrathecally.  A primary series of tetanus toxoid should be initiated, as disease does not protect against future infection.
4. Treat portal of entry – surgical debridement and antibiotics.  Penicillin is classically used but metronidazole is now used in Peru due to some data implicating penicillin as an antagonist of GABA [Ann Trop Med Parasitol. 2004 Jan;98(1):59-63], thereby decreasing benzodiazepine effectiveness.
5. General care – includes usual ICU considerations but also intense avoidance of light and stimuli as these readily precipitate reflex spasm.
6. Treat any sympathetic hyperactivity – labetalol or esmolol (combined alpha and beta blockade) seems best for this; alternatively, morphine or clonidine can be used.  A recent randomized controlled trial [Lancet. 2006 Oct 21;368(9545):1436-43] indicates that continuous magnesium sulphate infusion reduces the need for mechanical ventilation and improves control of muscle spasms and autonomic instability and this was initiated here on the first day of admission.