Case report Vacuolation and chromatolysis of lower motoneurons in tetanus A case report and review of the literature In recent years, the pathophysiological action of tetanus toxin has been extensively studied by many investigators.1,2 The role of the toxin in decreasing Samuel M. Chou, M.D., Ph.D. inhibitory input to alpha motoneurons is well known. Morphological alterations in neurons in Department of Pathology both clinical and experimental tetanus have not been consistently described. Indeed, several authors William N. Payne, M.D.* simply state that no changes are found. There are, however, reports of nuclear capping, and either chromophobia or chromophilia3 as well as central or perinuclear chromatolysis in motoneurons4,5 in tetanus. The finding of striking concurrence of cen- tral chromatolysis and vacuolation confined to mo- toneurons in a case of human tetanus prompts this report and a review of the literature. Case report A 58-year-old black man was admitted because of inability to swallow. The night before admission, he choked while trying to drink water; he also noted pain and stiffness in the neck and back. He was diabetic and took 40 units of insulin each morning. He had had an ulcer on his left heel for the preceding 10 months, but there was no history of recent wounds. He had not had a tetanus immunization for "many years." Chronic ulcers on the right leg had necessitated an above-the-knee am- putation l'/2 years before. The patient also had been * Section of Neuropathology, West Virginia taking phenytoin (Dilantin) and phenobarbital for a University Medical Center, Morgantown, West Virginia 26506. Supported in part by a grant from the Muscular Dystrophy Association. 255 Downloaded from www.ccjm.org on September 24, 2021. For personal use only. All other uses require permission. 256 Cleveland Clinic Quarterly Vol. 49, No. 4 seizure disorder, which apparently followed dition of the patient after withdrawal of a stroke for which he had had a carotid curare. Curare was stopped and atropine bypass. and neostigmine (Prostigmin) were given. The patient initially went to the emer- The patient became bradycardic, developed gency room of a local hospital and was found atrioventricular block as well as asystole and to have risus sardonicus, opisthotonus, and died. dysphagia; the clinical impression was early tetanus. He was transferred to West Virginia Autopsy findings Medical Center. Autopsy was performed three hours Physical examination revealed marked after death. The right lower leg of this opisthotonus and masseter muscle spasm to obese, well-developed black man had the degree that the mouth could not be opened. The patient was moderately irrita- been surgically amputated, and the ble and exhibited muscle spasms when stump was well healed and clean. An touched. There was rigidity and increased ulcerative wound measuring 3X4 cm tone of the paraspinal muscles. Examination was present over the lateral left heel. of the heart, lungs, and abdomen was unre- The heart weighed 400 g; examination markable. A 2 X 1-cm ulcer was found on revealed severe arteriosclerotic changes the lateral aspect of the left heel; there was of the coronary arteries, focal athero- increased muscle tone in the left leg. The matous segments narrowing the lumen. right leg demonstrated good stump healing A proximal segment of the left circum- with no ulceration. Cranial nerves were in- flex coronary artery was completely oc- tact with pupils equal and reactive; there cluded by two fresh brown thrombi. The was no papilledema. Sensory examination revealed decreased light touch and vibration posterior wall of the left ventricle dis- sense in the lower extremities; position sense played patchy areas of recent hemor- was normal. Deep tendon reflexes were nor- rhagic infarction. The aorta, however, mal and symmetrical; there was no Babinski had only mild atherosclerotic changes. sign on the left. The left lung showed marked consoli- Laboratory studies on admission revealed dation with microscopic findings of an elevated creatine phosphokinase (CPK) acute and subacute bronchopneumonia. of 700 U/L (normal, <125 U/L) that rose to Marked hepatosplenomegaly was pres- 1629 U/L five days after admission. The ent (liver, 23,500 g; spleen 650 g); mi- white blood cell count (WBC) was 11,200/ croscopically moderate chronic conges- mm3 with a left shift; hemoglobin and he- tion was noted. The gastrointestinal sys- matocrit were 13.8 g/dl and 43%, respec- tem was unremarkable. The kidneys tively. Serum electrolytes were normal; glu- showed the typical features of nodular cose was 70 mg/dl. Lumbar puncture re- vealed 880 erythrocytes, 3 leukocytes, and a intercapillary glomerular sclerosis char- glucose of 65 with a peripheral glucose of acteristic of Kimmelstiel-Wilson disease. 100. This was interpreted as a normal trau- The pancreas was both grossly and mi- matic tap. Culture of the ulcer on the left croscopically unremarkable, as were the heel grew Clostridium tetani. The patient was rest of the viscera. initially treated with 5000 units of tetanus Neuropathological findings. The brain immune globulin (Hyper-Tet) and intrave- weighed 1075 g, reflecting mild gener- nous penicillin (one million units every four alized cortical atrophy and focal cystic hours). The wound on the left heel was debrided. Following one generalized seizure encephalomalacia (2x3 cm) in the right he was transferred to the Intensive Care Unit temporo-occipital region. The basal cer- where he was treated with curare, and main- ebral arteries showed mild athero- tained on a respirator. Nine days after ad- sclerotic changes. The brain stem and mission, it was decided to evaluate the con- the spinal cord were macroscopically Downloaded from www.ccjm.org on September 24, 2021. For personal use only. All other uses require permission. Winter 1982 Vacuolation and chromatolysis 257 normal. Microscopically, the cortical spared (Figs. IA and 2A). No astrocytic neurons, including those of Ammon's reaction was noted in the vicinity of horn, showed no ischemic or senile affected neurons; neuronal loss was not changes. The right temporo-occipital apparent. No foci of perivascular de- cortex showed focal cystic astro- myelinative lesions or gliosis were noted. gliosis. The Betz cells in the motor strips Finely granular intravacuolar mate- appeared intact. Ascending tract degen- rials were visualized on silver impreg- eration was found throughout the spinal nation (Fig. 2A and B). Transmission cord, especially the gracilis; and the pos- electron microscopy (TEM) revealed terior spinal roots showed diffuse inter- that the vacuoles contained finely gran- stitial fibrosis. The anterior spinal roots ular or amorphous material and mem- were spared and showed no sign of mye- brane-bound vesicles, 0.5 to 1.0 ¡x in lin or axonal damage. Most striking was diameter, containing parallel helical the vacuolation concurrent with central fibrillar material (Fig. 3A and B) and chromatolysis, which was confined to flocculant densities. These vesicles were the motoneurons of both the brain stem considered to be altered mitochondria and spinal cord. The anterior horn mo- in the vicinity of vacuoles (Fig. 3C) toneurons of the spinal cord, especially where little autolytic change was seen in in the lumbar cord, were most severely other subcellular organelles. The vacu- involved; and almost all the anterior oles themselves were seldom lined by a horn motoneurons showed honeycomb- membrane. This impression was like multiple vacuolations (Fig. 1A and strengthened on scanning electron mi- B). The vacuoles measured 4-7 /x in croscopy (SEM) of the specimens pre- diameter and often contained fine gran- pared according to the method de- ules, which were readily seen in the scribed by Hamphery et al.6 Cryofrac- Bodian stain (Fig. 2A and B). They oc- tured control motoneurons (Fig. 4A) re- curred symmetrically throughout the vealed a finely granular fractured cyto- spinal cord; the severity of involvement plasmic surface without vacuoles; the increased caudally. The symmetric dis- nucleus with its chromatin and nucleo- tribution of lesions precluded the possi- lus was clearly identifiable. The vacu- bility of a secondary alteration from the oles in the honeycombed neurons (Fig. right above-the-knee amputation. The 4B) were lined by a finely granular yet neurons in Clark's columns, intermedi- relatively smooth surface without a olateral nuclei, and posterior horns were membrane. They infrequently dis- well preserved and free of vacuoles. The played fine linear or granular contents neurons in the brain stem motor nuclei over their surfaces (Fig. 4B, arrows), were also involved to a lesser extent; which corresponded in dimension to the motoneurons of XII, VII, and V dis- vesicles seen on TEM. played similar vacuolation. The neurons of sensory V, substantia nigra, reticular Discussion formation, locus ceruleus, and pontine gray were all intact. The vacuolation In his review of central nervous sys- was often superimposed on centrally tem (CNS) pathology in tetanus, Baker4 chromatolyzed large motoneurons. cited several investigators around the Chromatolysis (Fig. 1A and B), seldom turn of the century who had noted vac- without vacuoles, was also seen in the uolation in nerve cells. Miiller and anterior horns on both sides. Small neu- Jeschke7 concluded that for induction of rons in the anterior horns were generally the vacuolation in the anterior horn cells Downloaded from www.ccjm.org on September 24, 2021. For personal use only. All other uses require permission. 258 Cleveland Clinic Quarterly Vol. 49, No. 4 Fig. 1A. Large spinal motoneurons with multiple vacuoles in a honeycomb pattern; note relative sparing of small neurons; hematoxylin and eosin stain, X 360. B. Motoneurons demonstrating both vacuolation and central chromatolysis; Kluver-Barrera stain, X 360. (which was seen in 14 of 22 tetanus cases toneurons. Tetanus toxin may not be and in 2 of 50 cases without tetanus) essential since transient, rhythmic, and two factors, hypoxia and tetanus toxin, synchronous myoclonic contraction of should act simultaneously upon the mo- muscles secondary to an increased excit- Downloaded from www.ccjm.org on September 24, 2021.