Case 88

A floppy baby who later developed malignant hyperthermia

The patient was a 4600-g product of a 37-week gestation complicated by spotting, cramping, and viral infection. Medications during pregnancy included medroxyprogesterone acetate, penicillin G potassium, and phenobarbital sodium. Immediately after birth, the newborn was noticed to have paucity of movement and a weak cry, and he was treated for pneumonia with antibiotics.

At 3 weeks of age, he was profoundly weak. Minimal retractions of the chest and pectus excavatum were noted. Heart and lungs were normal. Generalized hypotonic included severe weakness in all four extremities, with retraction and adduction of the upper extremities and minimal movement of the shoulders. Proximal muscles were weaker than distal. Sensory examination was intact to pinprick. Deep tendon reflexes could not be elicited.

Laboratory studies included normal serum creatine kinase and normal nerve conduction velocities. On electromyogram there was an increased number of polyphasic potentials of short duration. A muscle biopsy specimen at 7 months of age was studied with a complete battery of histochemical stains and by electron microscopy. There was evidence of atrophy of both fiber types, but mainly of type I fibers; many fibers of primary type I had small areas devoid of oxidative enzyme activity ( Fig. 88-1 ), and there was no evidence of necrosis or phagocytosis. Electron microscopy showed that there were no mitochondria in the core areas and that the myofibers were disorganized.

At 9 months of age the patient would lie in a pithed frog position. By 18 months he could not sit independently but needed to prop himself on his arms. He attempted to crawl but could not support his body weight. He was fitted with a parapodium for standing. At 18 months of age there was evidence of a mild thoracic scoliosis, and a grade 1/6 systolic murmur was heard at the left sternal border. He had frequent respiratory tract infections, and at 28 months of age he developed congestive heart failure.

He was admitted for cardiac catheterization one month later and was premedicated with meperidine hydrochloride (Demerol), 20 mg intramuscularly and hydroxyzine hydrochloride (Vistaril), 10 mg intravenously (IV). Because he was irritable, he received ketamine hydrochloride 10 mg IV as well. Six milliliters of 1% lidocaine hydrochloride with epinephrine was used for local infiltration. Cardiac cath revealed an atrial septal defect with a large left–right shunt and mitral regurgitation. The child was transferred to the recovery room where he was lethargic, clammy, and pale with an axillary temperature of 37.3°C. One hour later, his rectal temperature was 40.9°C and his heart rate was 210 beats per minute.

He was treated with dantrolene sodium and cooling and was intubated. During the next 12 hours his condition gradually deteriorated. He was in shock with unmeasurable blood pressure despite maximum support including dopamine hydrochloride, epinephrine, sodium nitroprusside drip, sodium bicarbonate, calcium chloride, methylprednisolone sodium succinate (Solu-Medrol), glucose, and insulin. He remained hypotensive and 26 hours after cardiac cath had a cardiac arrest with no response to any form of resuscitation.

Pertinent autopsy findings were a patent foramen ovale, a fenestrated valve, dilated atrium, and a markedly hypertrophic right ventricle with some focal wall thickening and minimal fibrosis. Skeletal muscle specimen showed endomysial fibrosis with internal nuclei and many necrotic atrophic basophilic fibers. Although this specimen was not studied by histochemistry or by electron microscopy, the paraffin-embedded sections showed segmental areas of rarefaction that appear to be the multicores seen on histochemical preparation. The spinal cord appeared normal with the normal number of neurons in the anterior horns. Cultures from the heart and lung were negative.

Discussion

This patient was a floppy infant with histologic findings characteristic of multicore disease. Children previously described as having multicore disease presented with generalized hypotonia, diffuse weakness, decreased muscle bulk, and delayed motor development. Two patients had lordosis and one had a high arched palate. Most patients were not suspected of having muscle disease until 8 or 9 months of age when they were delayed in their ability to sit independently or to crawl. All ultimately became ambulatory but had great difficulty sitting up from supine and rising from a chair without handrails.

This case was noted to be extremely weak and hypotonic immediately after birth. Initially, a clinical diagnosis of Werdnig–Hoffmann disease was made. No DNA testing was available at that time. Muscle biopsy findings at 7 months of age were diagnostic for multicore disease. In contrast to other reported patients with multicore disease, this patient remained very weak. He was severely limited in motor skills, needing adaptive equipment to feed himself and external support for independent sitting, and a parapodium was prescribed to allow him to stand. At age 2 1/2 years, prior to developing congestive heart failure, there was no significant improvement in muscle strength to suggest that he was near the point of being able to walk.

One other reported patient with multicore disease had cardiac involvement and an atrial septal defect. Her course was much different, and at age 11 years, she had only limitations in bike riding and stair climbing. This case was asymptomatic from his cardiac disease from birth to 18 months of age, with a normal respiratory rate, heart rate, and without hepatosplenomegaly. He did have several upper respiratory tract infections between 18 and 28 months, which may have been related to his cardiac disease or his weak respiratory musculature. At 28 months, he developed congestive heart failure that was controlled with medication. In fact, he was asymptomatic of heart failure at the time of admission for cardiac catheterization.

Central core and multicore disease have some striking similarities in their pathologic lesions, and this could suggest related pathogenetic mechanisms resulting in these two diseases. Central core disease and multicore disease have been associated with malignant hyperthermia syndrome (MHS) during anesthesia. Multiple mini-core myopathies have variable phenotypes that are present in childhood or adolescence. The most typical presentation includes weakness, respiratory involvement, and spinal deformities. Those disorders are caused by mutations of the RYR1 gene of the ryanodine receptor affecting EC coupling.

The patient developed a high, unexplained fever, acidosis, and tachycardia after receiving lidocaine and ketamine agents previously associated with malignant hyperthermia. Hyperthermia could have been precipitated by medication or the stress of cardiac catheterization. He did not have muscle rigidity, elevated creatine kinase levels, or myoglobinuria as would have been expected for malignant hyperthermia. However, nonrigid forms of the syndrome have been described. Laboratory tests cannot identify all patients with his condition. Although the cause of death could have been an allergic reaction to the contrast media, or from sepsis, the clinical and autopsy findings do not support those diagnoses and the cause of death is more likely related to anesthesia.

MHS is a condition characterized by severe muscle rigidity, fever, cardiac arrythmia, and rhabdomyolysis. It occurs particularly with exposure to general anesthesia such as halothane and the paralyzing muscle relaxants. Other manifestations include acidosis, hypermetabolism, fever, hyperkalemia, cardiac arrythmia, and initial hyperkalemia and initial hypercalcemia due to intracellular calcium accumulation. The incidence of MHS is 1 in 1500 children and 1 in 50,00 adults. It is an usual autosomal disorder more frequently associated with the RYR1 mutation. It has also been reported in patients with the dihydropyridine voltage–gated calcium channel, and these voltage channels are involved in muscle calcium release. Attacks of MH are caused by the excessive release of calcium by the sarcoplasmic reticulum (SR) under certain conditions. The mutations of MH cells appear to lower the threshold for calcium release by the SR altering the excitation–contraction coupling.

During the attacks, the increased intracellular calcium causes muscle contractures that lead to increased oxygen consumption, glycogenolysis, and depletion of high-energy phosphate compounds with an elevation of body temperature. There is also limitation of calcium reuptake by the SR for muscle relaxation increasing muscle contractures with further increased intramuscular calcium accumulation ( Fig. 88-2 ). This results in leakage of phosphate and potassium into the bloodstream that can cause cardiac arrythmias. Serum uric acid and lactic acid, creatine kinase, and myoglobin are increased and can cause renal failure ( Table 88-1 ). It should be mentioned that although halothane and paralyzing skeletal muscle relaxants are the drugs more often implicated in triggering this disorder, several other medications have been reported to cause MHS.