Neuronal Intranuclear Inclusion Disease Presenting as Chronic Intestinal Pseudo‐Obstruction in the Neonatal Period in the Absence of Neurologic Symptoms

INTRODUCTION On the basis of histopathologic data, chronic intestinal pseudo-obstruction (CIPO) may be classified as neuropathy or visceral myopathy (1,2). Among the visceral neuropathies, neuronal intranuclear inclusion disease (NIID), a multisystem degeneration with onset in childhood, constitutes a very rare cause of CIPO in children (3). We present a case of NIID manifested by CIPO during the neonatal period in a 6-month-old girl. CASE REPORT A 6-month-old female was born at term by normal vaginal delivery to a 20-year-old primigravida mother with uneventful pregnancy. She passed meconium at 36 hours of life. At 15 days of life, she developed bilious vomiting associated with abdominal distension. Barium swallow and small bowel series showed dilated duodenum with no evidence of obstructive lesion. Barium enema showed a transitional zone at the rectosigmoid junction suggestive of Hirschsprung disease, but suction rectal biopsy confirmed the presence of ganglion cells. During hospitalization, the patient developed recurrent attacks of intestinal obstruction for which she was kept on total parenteral nutrition and erythromycin. Upper manometric evaluation was not performed at that time. Feeding with semi-elemental diet (Pregomin, Kolinska, Ljubljana, Slovénia) was started at the age of 1 month with progressive increment in its amount. Total parenteral nutrition was progressively tapered and stopped at the age of 3 months. The patient was maintained on semi-elemental diet in addition to the use of cleansing enemas. At the age of 6 months, she presented to our hospital with a history of high-grade fever of 2 days duration associated with vomiting feculant liquid, severe abdominal distension, and failure to pass flatus. Upon physical examination, the patient appeared to be in shock. The abdomen was severely distended and tense with absent bowel sounds. Fluid resuscitation was started with lactated Ringer's solution. The nasogastric tube aspirate was feculant. After rectal examination, the patient passed gas and foul smelling stool. Upright film of the abdomen showed multiple air fluid levels. Gastrograffin enema showed normal caliber of the colon with dilated terminal ileum. Exploratory laparotomy performed after stabilization of the patient showed normal caliber of the colon with diffuse dilatation of the small intestine with no evidence of obstructive cause. Multiple full-thickness intestinal, colonic, and rectal biopsies were taken at the same time. The patient was maintained on intravenous antibiotics, with nasogastric drainage and total parenteral nutrition. Eight days after laparotomy, the patient developed a second episode of intestinal obstruction that required a second laparotomy showing a narrowed zone in the terminal ileum. Loop ileostomy was performed at 40 cm from the ileocecal valve above the narrowed zone. On histopathology, few ganglion cells were seen in the sigmoid region, with scant cytoplasm associated with the presence of voluminous eosinophilic intranuclear inclusions. The smooth muscle was normal. The same pattern was seen in the colon, terminal ileum, and the appendix, confirming the diagnosis of NIID (Fig. 1). Neurologic examination was normal except for mild lower limb hypotonia. The electroencephalogram, ophthalmic examination, and spine radiographs were normal. Magnetic resonance imaging of the brain showed mild cortical atrophy more prominent in the Sylvian fissures.FIG. 1: Eosinophilic intranuclear inclusions seen within the entenc neurones in the color.The patient was kept on total parenteral nutrition. The ileostomy output ranged between 350 and 450 mL/d. She was started on intravenous erythromycin, but the ileostomy drainage increased dramatically, reaching 1,200 mL/d (200 mL/kg/d), so erythromycin was stopped. Feeding with semi-elemental diet (Pepti-junior Nutricia Cuijk B.V., Cuijk the Netherlands) was started 1 month postoperatively. The amount was increased progressively according to patient tolerance, the presence of sugar in the ileostomy fluid, and the amount of ileostomy output. The patient was discharged home at 11 months of age on enteral nutrition with semi-elemental diet because of insufficient oral intake. The ileostomy drainage ranged between 50and 100 mL/d upon discharge. Neurologic examination showed the persistence of mild lower limb hypotonia. Psychomotor development was adequate for her age. Follow-up neurologic examination at the age of 16 months showed no abnormal findings, with adequate psychomotor development. DISCUSSION Pediatric CIPO spans a spectrum from mild to severe disease. Usually, in the absence of underlying disorders, CIPO results from abnormalities of enteric smooth muscle (visceral myopathy) or the enteric nervous system (visceral neuropathy) (4). Among the visceral neuropathies, NIID is a very rare entity, with only few cases reported (5). It can be familial or it may occur as asporadic case. Our patient was the first baby of a nonconsanguineous couple in whom symptoms of CIPO began in the neonatal period with no family history of such disease. It is characterized by the presence of eosinophilic intranuclear inclusions of glial cells and neuronal loss throughout the central nervous system, ataxia, pupil modification, damage of the autonomous nervous system, and progressive tetraplegia. Symptoms usually begin in childhood and depend on the site of maximal neuronal loss. New-onset bulbar weakness, Parkinsonism, severe cognitive and motor deterioration, gait disturbance, motor slowing, and cerebellar degeneration may be the presenting features of the disease (3,6,7). Associated neurologic manifestations include amyotrophy, speech defects, and convulsive disorders. Scoliosis and spina bifida occulta with abnormal vertebral size are frequently found. Other rarely reported manifestations include cardiomyopathy, nystagmus, and oculogyral spasms (6,8). In our patient, the disease was manifested by intestinal obstruction in the neonatal period with subsequent CIPO. The neurologic examination was unremarkable except for mild lower limb hypotonia. The psychomotor development was normal. Barnett et al. (7) reported a family with visceral neuropathy related to NIID, but the disease began in childhood with abnormalities of the autonomic nervous system. To our knowledge, our case is the first reported case in the literature of NIID manifested by CIPO during the neonatal period in the absence of neurologic symptoms. Although most cases of NIID have been diagnosed postmortem, rectal biopsies may be diagnostic during life. Kulikova-Schupak et al. (9) reported two cases of NIID in children presenting with unexplained multisystem degeneration that was diagnosed by rectal biopsy. In our patient, the diagnosis was confirmed by rectal, colonic, and intestinal biopsies, even in the absence of neurologic manifestations. Several drugs have been reported in the literature to promote intestinal motility such as cisapride, metoclopramide, erythromycin, and octreotide. Because of side effects of the first two drugs, erythromycin is now considered as a first-line medical treatment but has little efficacy in patients with neurogenic CIPO (10). In our patient, the use of intravenous erythromycin was associated with a dramatic increase in the amount of ileostomy drainage, so it was stopped. This was the reason we did not try a course of octreotide. The role of surgery in CIPO remains uncertain. Proposals for treatment by different authors include the use of enterostomy, duodenojejunostomy, duodenoplasty, gastrostomy, and transplantation of small intestines (11,12). In our patient, ileostomy was sufficient to decompress the dilated intestines. The development of several modalities for treatment of patients with CIPO allows an extended survival of affected patients. The prognosis of NIID remains poor, with a high mortality rate secondary to neurologic deterioration. Because the disease was manifested by CIPO with little neurologic manifestation in our patient, the prognosis remains unknown. In conclusion, although most cases of NIID present in childhood with neurologic deterioration, our case highlights the role of the pathologist in making the diagnosis of this entity in patients with CIPO in the absence of neurologic manifestations.