Opsoclonus myoclonus syndrome (OMS), first described by Marcel Kinsbourne in 1962, occurs following infection, a paraneoplastic process, or in association with neuroblastoma. Myoclonus may involve the limbs, trunk, and face, varying from tremulousness to coarse multifocal jerks, and is often exacerbated by movement or emotional distress. Opsoclonus refers to conjugate, rapid, and intermittent oscillating eye movements. Hyper-IgM (HIGM) syndrome is an X-linked disorder which causes primary immunologic deficiency. Patients present with repeated opportunistic infections due to deficient immunoglobulin class switching. The anesthetic implications of each of these rare syndromes should be carefully understood in order to optimize perioperative care of a patient with both, particularly in regard to immunosuppression in an immunocompromised patient with an elevated cancer predisposition. The patient’s family has provided written informed consent for publication of this case report.

A 5-year-old, 20 kg male presented to the emergency department at Westchester Medical Center with a 2-day history of right lower quadrant pain and was subsequently diagnosed with acute appendicitis on ultrasound. His past medical history was significant for OMS, which was diagnosed at 17 months due to gait instability, drooling, upper extremity myoclonus and new onset nystagmus. His motor skills have subsequently improved, however he still has minor delays in gross motor skills such as unsteadiness when walking. Subsequent genetic testing also revealed HIGM syndrome, requiring monthly intravenous immunoglobulin (IVIG) therapy. He was previously treated with granulocyte-colony stimulating factor for neutropenia. Lab results revealed a hemoglobin of 8.5g/dL, platelets of 41x10⁹/L, white cell count of 2.9x10⁹/L, neutrophils of 7.5x10⁹/L, lymphocytes of 13.9x10⁹/L, and monocytes of 12.9x10⁹/L. His last dose of IVIG was over five weeks ago.

He was taken emergently to the operating room for a laparoscopic appendectomy. Standard ASA (American Society of Anesthesia) monitors were applied, and the patient was induced via his peripheral IV with propofol 3mg/kg and rocuronium 1.2mg/kg. He was intubated without difficulty with direct laryngoscopy using a Miller 1.5 blade and a 5.0mm cuffed endotracheal tube. Platelets were transfused prior to surgical incision at 20 mL/kg. A complete blood count was sent off following induction to guide the patient’s IVIG therapy. Anesthesia was maintained with total intravenous anesthesia (TIVA) using propofol to attenuate the immunosuppressive effects of surgery. Similarly, opioids were avoided to decrease the risk of immunosuppression. Prophylactic antibiotics were given prior to incision. At the conclusion of surgery, the patient was reversed with 2mg/kg of sugammadex and extubated without incident. A transverse abdominis plane block was performed as a nonopioid analgesic management option.

During the surgery, an incidental mass was found near the appendix, with histology confirming florid follicular lymphoid hyperplasia. He was seen by pediatric hematology-oncology and his IgM B cells were noted to be increased and incapable of responding to immunization antigens. His pneumococcal titers were negative, indicating his susceptibility to pneumococcal infections. Flow cytometry revealed markedly decreased IgG and IgA carrying B cells. Helper cells were increased and CD4/CD8 ratio was increased. These results were all consistent with HIGM syndrome. He was also started on IVIG, to make up for his missed scheduled dose. He experienced no post-procedure complications.

Age of onset for OMS is usually between 18-24 months and it affects 1 in 10,000,000 people annually, with a slight predilection for the female sex [1]. It occurs in about 3% of all children with neuroblastomas [2]. Brain histology reveals widely distributed perivascular lymphocyte infiltration [3]. Prognosis for OMS tends to be poor; most children have significant learning disabilities and moderate to severe cognitive impairment. OMS patients exhibit irritability, inconsolable crying, loss of developmental milestones, dysarthria, sleep disturbances, and reduced sociability. Three out of the following four criteria are required for diagnosis: (1) opsoclonus, (2) myoclonus/ataxia, (3) behavioral change or sleep disturbance, and (4) neuroblastoma. Mainstay of therapy includes corticosteroids, immunosuppressive treatments such as intravenous immunoglobulin (IVIG), corticotropin, cyclophosphamide, cyclosporine, azathioprine, plasmapheresis, and rituximab [3]. Surgical resection is indicated if a tumor is present. Differential diagnosis includes Sydenham chorea, cerebellar ataxia, seizure disorder, brain injury, viral infections, and metabolic or toxic disorders.

There are numerous anesthetic considerations in a child with OMS. Preoperative evaluation of all children with OMS should preclude the presence of a neuroblastoma. The anesthesiologist should rule out lung consolidation, pleural effusions and deviation or compression of the trachea and great vessels. Catecholamine levels should be checked in the setting of a neuroblastoma prior to surgical manipulation to avoid hemodynamic instability. A central neuraxial anesthetic should be avoided if there is invasion of the intravertebral space by a paravertebral tumor. Chronic corticosteroid therapy may necessitate perioperative steroid supplementation. Burrows et al. [4] described worsening of opsoclonus and myoclonus with ketamine, etomidate and meperidine, which should be avoided in these patients. Lee et al. [5] utilized propofol and remifentanil for total intravenous anesthesia and noticed that both opsoclonus and myoclonus disappeared as the target concentration was achieved. Following treatment, relapse of disease can occur with anesthesia, fever, stress, discontinuation of immunotherapy, or following immunizations [6].

Hyper-IgM syndromes are a very rare group of X-linked disorders which cause primary immunological deficiency, first described by Rosen et al., in 1961 [7]. Data from the national registry in Spain suggests a prevalence of 1 in 2,000,000 live births [8]. X-linked HIGM syndrome, which accounts for 60-75% of cases, is caused by a variation in the gene CD40LG, which results in a reduction or abnormal formation in CD40 [9,10]. Overall prognosis is poor, with a survival rate of 29.2% at age 40 in one study and 20% survival by age 25 in another [10]. Due to this altered CD40 production, the T-cells of these patients are not able to bind with CD40 on the surface of B-cells, which prevents sequential production of other immunoglobulins. As a result, patients have an excessive quantity of IgM, and deficient quantities of IgG, IgA, and IgE. This lack of class switching of immunoglobulins makes patients with HIGM syndromes very susceptible to repeated opportunistic infections, particularly sinopulmonary and gastrointestinal infections [10].

Consistent with other primary immune deficiencies, these patients have poor response to pathogens, which makes them less effective at identifying and suppressing cancerous growth [11]. Malignancies associated with HIGM syndrome include leukemias, gastrointestinal tract and hepatocellular carcinomas, cholangiocarcinomas, neuroectodermal and pancreatic tumors [11]. In a patient with co-existing OSM, there is a particularly high risk for neuroblastoma. HIGM syndrome is linked to autoimmune diseases such as neutropenia, hemolytic anemia, arthritis, hypothyroidism, inflammatory bowel disease, and renal disease [10,11]. The diagnosis is largely based on clinical and family history.

The anesthetic management of HIGM syndrome involves careful application of sterile technique for infection prevention and surveillance [12]. Due to patients’ immunocompromised status, antibiotic prophylaxis should be considered for most procedures [13]. Of note, HIGM patients may not be able to mount a classic immune response with fever or neutrophilia. Patients on regular IVIG (half-life of 2-3 weeks) therapy should receive this treatment in the perioperative period, as it reduces the risk of infection and lymphoid hyperplasia. HIGM patients are at increased risk of hemolytic anemia, autoimmune thrombocytopenia, or idiopathic thrombocytopenic purpura [9,10]. IVIG can be helpful in these situations, and although the rise in platelets may only last for a few days to weeks, this may provide a window for safe surgical intervention [14]. In emergent cases where IVIG treatment is not feasible preoperatively, performing minimally invasive surgery may potentially decrease the risk of bleeding. Splenectomy or treatment with rituximab may be necessary in some cases [12]. Ultimately, the only curative therapy is allogeneic hematopoietic stem cell transplant [11]. Post-operatively, IgG levels may be diminished, especially if the patient is hypovolemic secondary to hemorrhage, burn injury or fluid loss.

Patients with poor respiratory function should undergo spirometry studies prior to elective surgery, as they may exhibit bronchiectasis from chronic respiratory insult due to immunodeficiency [12]. Chronic hepatitis and liver cirrhosis from infections such as cryptosporidium parvum may cause hepatic failure, which can affect clearance and metabolism of anesthetic agents. Liver function tests should also be considered for elective procedures in such patients [10].

Surgical stress releases hormones such as catecholamines, adrenocorticotropic hormones, and cortisol, which inhibit proinflammatory cytokines such as interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha, while stimulating angiogenic factors that can cause initiation or recurrence of cancer [15,16]. In an immunocompromised patient with HIGM and increased cancer risk secondary to both OSM and HIGM, we utilized an anesthetic technique that attenuated immunosuppression. Multiple studies have described the influence of cell-mediated immunity, cytotoxic T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages on tumor surveillance, with human studies suggesting that low perioperative NK cell activity is associated with increased cancer morbidity and mortality [17-19].

Compared to volatile anesthesia and other intravenous anesthetics like ketamine and thiopental, propofol has been shown to be better at attenuating the surgical-stress response and does not attenuate NK cell activity as severely, therefore TIVA with propofol was utilized in this case [20-22]. A 2019 meta-analysis showed improved cancer recurrence rates and survival for patients who received propofol-based TIVA compared to volatile anesthesia [20]. Opioids inhibit T-cell proliferation and decrease NK cell activity, although these effects are most noticeable in non-synthetic opioids such as morphine [23,24]. Opioid-free analgesia was utilized in this case, with regional anesthesia performed for analgesia. Local anesthetics inhibit excessive inflammatory response from granulocytes, monocytes, and macrophages, while not significantly impairing host immunity, however there is not yet any clear evidence in human studies that confirms a benefit in cancer incidence and recurrence rates from regional anesthesia [25].

The patient with OSM and HIGM can provide multiple challenges for the anesthesiologist, particularly when presenting in tandem. Patients with OMS should have the diagnosis of neuroblastoma excluded, and neuroexcitatory anesthetic medications such as ketamine, etomidate, and meperidine should be strictly avoided. TIVA may be utilized in a patient with active symptoms to control opsoclonus and myoclonus. IVIG is likely to be beneficial for both OSM and HIGM. Many patients with HIGM are chronically immunocompromised and exhibit multi-organ involvement secondary to their disease process. Non-immunosuppressive anesthetics can be utilized to reduce the risk of post-operative infection. While the cellular and humoral suppressing effects of surgery and anesthetics may be insignificant in immunocompetent patients, they may have serious implications in those with pre-existing immunodeficiencies. Anesthesiologists must be aware of the unique challenges that this combination of syndromes can present, and how best to manage them.

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Cynthia Wong: This author helped write and edit the manuscript. Irim Salik: This author helped write and edit the manuscript.