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The Gorgas Courses in Clinical Tropical Medicine are given at the Tropical Medicine Institute at Cayetano Heredia University in Lima, Perú.  Each August we run one of our 2-week refresher courses for those with previous training in tropical medicine; currently running is the Gorgas Advanced Course.  For the past 11 years, we have been pleased to share interesting cases seen by the participants during the weeks of the year one of our courses is in session; there will be one more case next week to complete the 2011 case series.  Each case includes a brief history and digital images pertinent to the case.  A link to the actual diagnosis and a brief discussion follow.

History:  51 yo male patient who 7 days prior to admission develops lumbar rigidity and pain which progressively increases and radiates to the abdominal wall.  Four days later has an onset of fever and trismus.  These symptoms progress and episodic muscle spasm with opistotonus (arching of the back) with less intense spasm in the limbs ensues.  No important past medical history.

Epidemiology:  Born and lives in an Inter-Andean valley outside of Lima.  Works as a farmer.  Does not remember his vaccination history.

Physical Examination:  T: 38.2°C  HR: 78  RR: 22  BP: 110/70 mmHg.  Generalized muscle rigidity, less intense in limb.  Spontaneous episodic trismus [Image A] and muscle spasm in back and legs [Image B].  Rest of the PE unremarkable.

Laboratory Results:  Hb: 13.8g/dL  Ht: 41.4%  WBC: 7830/uL Bands: 71% Lymphocytes: 19%  Platelets: 243,000/uL  Glucose: 117mg/dL  Creatinine: 1.0mg/dL  Urea: 76mg/dL  Calcium: 8.8mg/dL  Na: 155mmol/L  K: 3.5mmol/L  Cl: 119 mmol/L  Total protein: 5.6 mg/dL  Albumin: 2.7mg/dL  AST: 65U/L  ALT: 71U/L  ALKP: 53 U/L (N<126)  CPK: 1469U/L  Urine: d:1.030  pH: 5.0.

Discussion:  A small wound was present [Image C] on the palmar base of the 4th finger of the right hand.  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 (not elicited in up to 20%), 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, parotitis, odontogenic abscess, peritonsillar abscess, retropharyngeal abscess, and traumatic injury, but in these cases trismus is due to pain and there is usually fever, whereas in tetanus trismus is due to masseter rigidity and initially there is no fever.

Disease is caused by a toxin, tetanospasmin, released by Clostridium tetani that 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, intramuscular injections, and burns).

Management is complex and must be done in a well-equipped Intensive Care Unit (ICU).  Non-ICU care in severe cases is associated with high 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.  For those with poor prognostic signs, where even survivors will require weeks of intensive care while synapses regenerate, immediate or early tracheostomy is advised.  Our patient was intubated two days after arrival due to difficulty controlling spasms and salivary secretions, and tracheostomy was performed one day later.
2. Relaxation-Sedation – must be titrated to eliminate reflex spasm.  Large amounts of diazepam, up to 20 mg/kg/day by IV bolus combined with chlorpromazine have been used.  Patients are relatively refractory to the sedating and respiratory depressive effects of diazepam. Midazolam is increasingly used.  A recent randomized controlled trial [Lancet. 2006 Oct 21;368(9545):1436-43] indicates that continuous magnesium sulphate infusion improves control of muscle spasms and autonomic instability and reduces the need for mechanical ventilation.  Magnesium sulphate can be combined with diazepam to improve control.  If this regimen does not control spasm, 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 should be given intramuscularly.  Some centres 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 has classically been used but metronidazole is now used in Perú 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 – among beta blockers, esmolol is preferred due to its short half life; combined alfa and beta blockade has also been used.  Alternatively, morphine or clonidine with or without magnesium sulphate can be used.