POLIP Syndrome

POLIP is an acronym that stands for: Polyneuropathy, Ophthalmoplegia, Leukoencephalopathy, and Chronic Intestinal Pseudoobstruction and consider a mitochondrial myopathy characterized by a tetrad of progressive sensorimotor peripheral nerve disease. Other clinical features include myopathy, diffuse leukoencephalopathy, and ptosis.

Myoneuro-Gastrointestinal Encephalopathy Syndrome; MNGIE Syndrome.

Very rare; 33 patients up to 1997.

There were suggestions that this disorder is an autosomal recessive trait with pathology of the nuclear genome, probably involving the control of the mitochondrial DNA replication (multiple deletions of mitochondrial DNA). Sporadic cases were also reported. Recent report of the MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) locus at 22q13.32qter.

The precise etiology and pathophysiologic significance of the mitochondrial DNA (mtDNA) deletions and the heterogeneity of the modifications of the mtDNA remain unknown. A mutation in the gene encoding thymidine phosphorylase possibly results in a defect of cytochrome c oxidase in liver and muscle.

MRI and CT scans are consistent with leukodystrophy involving the cerebral and cerebellar white matter. Histology shows widespread endoneurial fibrosis and demyelination in the peripheral nervous system. Muscle biopsy with histologic features of mitochondrial myopathy (ragged red fibers, muscle fibers with increased succinate dehydrogenase stain or ultrastructurally abnormal mitochondria). Biochemical examination of the liver and muscle tissues reveals defect of cytochrome c oxidase (complex IV of the respiratory chain). Nerve conduction and electromyographic (EMG) studies are compatible with a sensorimotor neuropathy; quantitative EMG may show a myogenic process. Southern blot analysis reveals multiple deletions of mtDNA.

Symptoms begin before age of 20 years. The first signs are gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea with intestinal dysmotility) in the majority of cases, or an ophthalmoparesis in some cases. The neurologic manifestations are predominantly outside the central nervous system (CNS); gastrointestinal (GI) dysmotility is a result of severe visceral neuropathy. Gastrostomy or jejunostomy tube feeding may fail because of dysmotility. Malabsorption with intermittent diarrhea and chronic malnutrition ensues. Parenteral alimentation is often necessary. Lactic acidosis after moderate glucose loads may occur. Prokinetic agents, including erythromycin and cisapride, are unsuccessful in improving intestinal motility. Visual disturbances may manifest as blepharoptosis and ophthalmoparesis. Proximal muscle weakness and mild ataxia is common. Neurosensory hearing loss, proximal myopathy with marked muscle atrophy, polyneuropathy, and encephalopathy (with hypodense areas in the white matter on MRI examination) are present. In addition, there also may be an autonomic neuropathy. Electrocardiography may show cardiac conduction abnormalities. Respiratory function may be severely affected. The prognosis is poor because of a severe weight loss bordering on cachexia, with a mean survival age of 28.5 years. The prognosis seems to be worsened by a young age of onset.

The diagnosis of mitochondrial disease should be considered in any child with a multisystem neurological disorder or who is being investigated for hypotonia. Anesthesia-related morbidity and mortality risk is essentially linked to the preoperative status of the child, that is, the number and extent of organ dysfunction. Avoid any elective anesthesia/surgery in the presence of infection or temperature because cytokines (mainly tumor necrosis factor) inhibit some complex of the respiratory chain. The following should be carefully evaluated: CNS: seizures, myoclonus, strokes, swallowing problems; metabolic: usual venous or arterial concentration of lactates and glucose; muscles: hypotonia, contractures, scoliosis; cardiac: even if the child is asymptomatic, ECG and echocardiography to exclude for conduction disorders and cardiomyopathy, respectively; if a pacemaker has been inserted, check it to be sure that it is functioning properly; pulmonary: frequent infections, chronic aspiration, pulse oximetry breathing room air, obstructive and/or central apnea; reduced ventilatory drive is common and many patients have an abnormal response to both hypoxia and hypercarbia; deaths have been reported following sedation with chloral hydrate or diazepam; hepatic and renal function must be evaluated; nutritional status and diet (glucose and/or lipid rich), tolerance to fasting and treatment (carnitine, vitamin Q, antiepileptic drugs).

Usual treatment must be maintained until the morning of surgery. Preoperative fasting must be kept as short as possible; if fasting is usually poorly tolerated, a glucose-containing solution should be started when fasting period begins. A sedative premedication is best avoided because of the possible abnormal response to hypoxia/hypercarbia. Induction: according to the anesthesiologist's choice; sevoflurane is the best choice for inhalation induction; propofol seems the best choice for IV induction but a 2% solution should be used to lessen the lipid load. Opiates: The dose should be carefully titrated according to the patient's needs. Muscle relaxant: Published data are often contradictory. Even in the absence of clinical myopathy, the patient's muscular response to nerve stimulation should be measured before administering a muscle relaxant. Atracurium or cis-atracurium are the best choice because of their spontaneous degradation. In case of myopathy, succinylcholine should not be used so as to avoid producing rhabdomyolysis. There is no evidence of an increased risk of malignant hyperthermia; however, one should be careful in the presence of confirmed myopathy. Intraoperative fluids: Avoid infusion containing lactates such as Ringer lactate or Hartmann solution, but give the patient a glucose (5 or 10% according to blood sugar level) solution. Aim for normoglycemia because hyperglycemia can also increase lactate production. Monitor (arterial or venous ) blood gases and lactate levels; in case of severe lactic acidosis use dichloroacetate 50 mg/kg IV over 30 minutes to stimulate pyruvate dehydrogenase to metabolize lactate in pyruvate. Perimedullar locoregional anesthesia can be used, but its cost:benefit ratio should be evaluated, taking into account the presence of severe scoliosis or of degenerative lesions in the spinal cord. Some patients with mitochondrial disease also present with axonal neuropathy of peripheral nerves; the possible effects of local anesthetics on these nerves are unknown. Prevention of hypothermia is important to avoid shivering and to increase oxygen consumption upon awakening.

Patients with mitochondrial disease are very sensitive to the respiratory effects of sedatives. It also seems, according to BIS measurement, that children with an anomaly of complex I of the respiratory chain are much more sensitive to the hypnotic effects of sevoflurane. Most studies performed on isolated mitochondria use doses of anesthetic agents far in excess of those used in daily practice and their clinical relevance is thus often dubious.