Nausea and Vomiting as Initial Manifestations of Pediatric NMOSD

Abstract

Intractable nausea and vomiting are commonly attributed to gastrointestinal (GI) conditions but can sometimes be a symptom of an underlying central nervous system disease. One potentially overlooked neurologic cause of intractable nausea and vomiting that is refractory to antiemetics is area postrema syndrome (APS). APS is a condition characterized by lesions of the dorsal caudal medulla and is considered a core clinical feature of neuromyelitis optica spectrum disorder (NMOSD). APS is present in up to 30% of patients ultimately diagnosed with NMOSD and can be the first presenting symptom of NMOSD in 12% of patients, as our case illustrates. Importantly, APS is highly responsive to immunotherapy. We present the case of a 14-year-old female with a history of migraines who presented to the emergency department multiple times for persistent nausea, vomiting, and hiccups. Multiple GI diagnoses were considered until she developed additional neurologic symptoms that prompted further workup and revealed the final diagnosis of NMOSD-APS. We posit that NMOSD-APS should be considered in the differential diagnosis for patients with intractable nausea and vomiting, especially in patients with a negative GI workup result and poor response to antiemetics.

Case Report

A 14-year-old Black female with a history of migraines presented to the emergency department (ED) with 9 days of nausea and vomiting that was not responsive to ondansetron and famotidine. Her family history was pertinent for maternal systemic lupus erythematosus. Her lipase level, which was obtained to assess for acute pancreatitis, was mildly elevated to 150 U/L. A chemistry panel result was negative for metabolic disturbances, a complete blood count with differential was normal, and a urine pregnancy test result was negative. She was discharged but returned to another ED the next day with persistent symptoms. Urinalysis revealed no signs of kidney stones or pyelonephritis, a comprehensive metabolic panel was normal, an abdominal radiograph to assess for small bowel obstruction or constipation was unremarkable, and she was discharged with a presumptive diagnosis of viral gastroenteritis. Her symptoms persisted, and she was directly admitted to the hospital 4 days later for further management. She was treated for 3 days with aprepitant, cyproheptadine, and intravenous fluids. Differential diagnoses for her symptoms included functional nausea, post-viral gastroparesis, and rumination syndrome. She was discharged with a referral to a gastroenterologist. Subsequently, she developed double vision, paresthesias of her lower extremities, constipation, and difficulty with gait that prompted a fourth ED visit, 11 days after the initial onset of symptoms and an 8-kg unintentional weight loss.

A neurologic examination in the ED was notable for bilateral end-gaze horizontal nystagmus, paresthesias on both plantar regions but no other sensory deficits, and ≥1 deep tendon reflexes at the Achilles tendons. A bedside ophthalmologic examination confirmed end-gaze nystagmus and revealed no loss of afferent visual function testing, manifest heterotropia, or optic disc edema. All other components of the neurological examination were normal. An MRI scan of the brain and orbits with contrast to assess for neurologic causes of vomiting revealed bilateral optic neuritis and a T2 hyperintense lesion involving the bilateral dorsal cervicomedullary junction consistent with APS (Fig 1). An MRI scan of the cervical and thoracic spine with contrast was obtained to evaluate for additional demyelinating lesions in the spinal cord and revealed subtle enhancement of the anterior horn gray matter, which is suggestive of longitudinally extensive transverse myelitis (Fig 1). Routine cerebrospinal fluid chemistries and meningitis/encephalitis panels were negative. Serum anti-aquaporin 4 (AQP4)-Immunoglobulin G(IgG) and anti-myelin oligodendrocyte (MOG)-IgG titers were obtained. Serum vitamin D 25-hydroxy levels were 16 ng/mL (normal, 30 to 120 ng/mL).

FIGURE 1.

A, Orbit MRI revealing T2 hyperintense lesions of both optic nerves. B, C, Brain MRI revealing T2 FLAIR hyperintense and T1 hypointense lesions in the area postrema. D, MRI of the cervical spine revealing subtle contrast enhancement along the ventral surface of the spinal cord from C1 to C4.

The patient was treated empirically with 1 g of intravenous methylprednisolone per day for 5 days and reported significant improvement in her symptoms. She was then discharged with follow-up in a neuroimmunology clinic. After discharge, the patient’s anti-AQP4-IgG titers resulted at 1:10 000; anti-MOG-IgG titers were negative. The patient presented to the clinic 12 days later and reported the resolution of all of her symptoms other than residual paresthesias. On retrospective review of systems, the patient revealed that she also suffered from intractable hiccups but was not asked by previous providers about the presence of hiccups accompanying her intractable nausea and vomiting. At the outpatient ophthalmology follow-up, she had no perimetric loss, no sign of optic atrophy on optical coherence tomography, and only a small right hypertropia in the pattern of right trochlear nerve paresis. She was then started on chronic immunomodulatory therapy to achieve sustained B-cell depletion with rituximab 375 mg/m² biannually.

Discussion

Nausea and vomiting are problems that are frequently assessed by general pediatricians and emergency medicine physicians. Common causes of nausea and vomiting include infectious gastroenteritis, postinfectious gastroparesis, small bowel obstruction, diabetic ketoacidosis, migraine, and increased intracranial pressure. APS, characterized by lesions of the area postrema, is a comparatively rare and underrecognized cause of nausea and vomiting. Different pathologies, including stroke, tumors, multiple sclerosis (MS), and MOG antibody-associated disease, have been reported to cause APS,¹ although it is most commonly associated with NMOSD.^2,3,4,5

NMOSD is an acquired, relapsing CNS demyelinating disease caused by antibodies targeting the water channel protein, AQP4.⁶ Unlike MS, disability in NMOSD is accrued with each attack, so prompt treatment with maintenance immunomodulatory therapy is of the utmost importance. Pediatric NMOSD is estimated to account for 3% to 5% of all NMOSD cases.⁷ In addition, it is estimated that APS is the initial manifestation of NMOSD in up to 12% of patients.⁸ The area postrema is a highly vascular structure located in the dorsal caudal medulla that abuts the fourth ventricle and functions as the “vomiting center” of the brain. Critical to its function, it lacks tight junctions between endothelial cells, allowing the detection of pathologic bloodborne chemicals to mediate vomiting. The capillaries in the area postrema are fenestrated, which is thought to explain why this region could serve as a portal for circulating antibodies, including AQP4-IgG, into the CNS.⁹ AQP4 is the most common water channel in the brain. It is expressed at the foot processes of astrocytes and plays a crucial role in regulating the water content of CSF and blood in the brain. Antibodies against AQP4 are pathogenic in NMOSD and the resulting complement-mediated inflammatory damage of oligodendrocytes in the AQP4-enriched area postrema, which is thought to be the pathologic substrate for APS. Pathologically, lesions of the area postrema in NMOSD have a relative lack of necrosis and demyelination compared with lesions of the optic nerves and spinal cord, potentially explaining why APS is relatively more responsive to immunotherapy.⁹

Our patient was initially diagnosed with relatively common causes of nausea and vomiting at her first 3 hospital presentations, including viral gastroenteritis, gastroparesis, and functional nausea. In contrast, NMOSD is much rarer, but misdiagnosis can lead to marked delays in management and increased patient morbidity. Further complicating the diagnostic challenge, APS is the initial presentation of NMOSD in some patients, preceding symptoms of optic neuritis, transverse myelitis, and other demyelinating syndromes.¹⁰ As a result, patients who are retrospectively found to have APS as an initial manifestation of NMOSD frequently evade diagnosis until they develop more obvious neurologic symptoms, such as visual disturbances and weakness.¹¹ In the right clinical setting, it is important that providers suspect NMOSD even in the absence of these more classic demyelinating symptoms. Case reports in both the adult and pediatric literature emphasize the importance of having a high index of suspicion for the early diagnosis of APS.^12,13 Shared features of patients first presenting with APS include several weeks of symptoms before diagnosis and significant weight loss. Other commonalities include frequent misdiagnosis with GI conditions despite extensive negative GI workup, poor response to antiemetics, and rapid response to immunotherapy, such as methylprednisolone.¹⁰ Hiccups are also present in most patients with APS and are often intractable.¹⁰ Pertinent negatives, such as the absence of significant abdominal pain, constipation, and diarrhea, may also point to the correct diagnosis. Indeed, our patient exhibited all of these features before her diagnosis of NMOSD-APS. In summary, general pediatricians and emergency medicine physicians should consider APS in the differential diagnosis of children who present with intractable nausea and vomiting and have a negative GI workup result for common etiologies, a poor response to antiemetics, subacute symptom worsening, intractable hiccups, or accompanying focal neurologic signs or symptoms (Table 1).

TABLE 1.

Features of APS Versus Other Causes of Nausea and Vomiting

	Onset	Vomiting	Signs and Symptoms	Triggers	Antiemetic Efficacy	Associated Conditions	Diagnostic Evaluation*	Treatment	Diagnostic Clue
APS	Sudden and severe	Frequent, persistent, and lasts >48h	Headache, dizziness, visual changes, hiccups	No specific triggers	Usually ineffective	Autoimmune, inflammatory, stroke, mass involving the area postrema	Brain MRI	Treat underlying condition (eg, steroids)	Intractable nature of nausea and vomiting, concomitant hiccups and neurologic manifestations
Migraine	Gradual, +/− aura	With or without headache	Photophobia, phonophobia	Stress, dehydration, sleep deprivation, and hormonal changes	May provide relief	Personal history of motion sickness, infant colic and family history of migraines	Evaluation for migraine features	Analgesics, antiemetics, intravenous hydration when needed	Family history of migraines Improvement with migraine treatment
Increased intracranial pressure	Gradual	With or without headache	Headache, altered mental status, papilledema, abnormal neurologic examination (such as dysmetria, ataxia)	Physical exertion, Valsalva maneuver	May provide temporary relief	Intracranial tumors, hydrocephalus	Neuroimaging +/− lumbar puncture	Management of intracranial pressure, underlying cause	Vomiting without nausea, papilledema, abnormal neurologic examination
Infectious gastroenteritis	Varies depending on etiological agent	Varies	Abdominal pain, diarrhea, bloating, malaise, fever	Food intake, infections	May provide relief	Gastroenteritis, food allergies, food intolerance	Laboratory tests if needed	Supportive in most cases	Positive contact, other family members with similar symptoms, accompanying diarrhea
Postinfectious gastroparesis	Gradual	Frequent	Abdominal pain, bloating, early satiety	Not typically triggered by specific factors	May provide relief but may be ineffective	Postinfectious	Clinical history, gastric emptying studies	Symptomatic relief (antiemetics, prokinetic agents, analgesics), dietary modifications	Symptom onset within a few weeks after a viral infection, early satiety, and bloating
Cannabinoid hyperemesis syndrome	Recurrent episodes	Frequent	Abdominal pain, hot showers relieve symptoms	Cannabis use	May provide temporary relief	Chronic cannabis use	Clinical history, urine drug screen	Cessation of cannabis use, supportive care	Trigger by cannabis use, relief of symptoms with hot showers
Diabetic ketoacidosis	Gradual	Frequent	Abdominal pain, polyuria, polydipsia, altered mental status	Illness, skipped insulin, stress	Usually ineffective	Diabetes	Blood glucose, ketones, blood gas	Insulin therapy, fluid resuscitation	Kussmaul breathing pattern, laboratory findings consistent with diabetic ketoacidosis, improvement of abdominal pain and vomiting with resolution of ketosis

* In addition to comprehensive clinical history and examination.

There are several aspects worth highlighting in our patient’s presentation, risk factors, and prognosis. One challenging aspect in this case was the normal ophthalmologic assessment (fundoscopic examination, visual fields, and optical coherence tomography), despite the clinical manifestation of optic neuritis and prominent imaging findings revealing bilateral posterior optic nerve T2 hyperintensities (Fig 1). This underscores the limitations of fundoscopic examination to detect posterior optic nerve involvement, which is not uncommon in NMOSD.¹⁴ Additionally, although optical coherence tomography has high sensitivity to detect optic neuritis, it can be normal in early stages of NMOSD-ON or with posterior segment lesions.¹⁵ Regarding the maternal history of systemic lupus erythematosus, it is well established that the cooccurrence of systemic autoimmunity is higher in NMOSD compared with MS.^16,17 Recognition of the high cooccurrence of systemic autoimmunity in NMOSD may have treatment and prognostic implications in our patient should she go on to develop evidence of systemic autoimmunity. Finally, although the diagnostic odyssey in our patient could have been abbreviated with a high clinical index of suspicion, increasing attention has turned to racial and ethnic health disparities in NMOSD, particularly for Black individuals and women. Further studies are needed to characterize in greater detail the role of social determinants of health in ethnic and racial health disparities and patient outcomes in acquired demyelinating diseases of the CNS.¹⁸

Therapeutically, APS may be more responsive to immunotherapy than other clinical syndromes seen in NMOSD, underscoring the importance of prompt recognition.⁹ In addition, unlike other acquired demyelinating diseases (eg, MS), neurologic disability in NMOSD accumulates with each attack with poorer recovery and increased risk for permanent disability. Therefore, the timely recognition of NMOSD-APS can directly affect patient outcomes by facilitating more prompt initiation of chronic immunotherapy. Although no US Food and Drug Administration-approved therapies for pediatric NMOSD exist, 3 medications, eculizumab (a complement C5b inhibitor), satralizumab (an IL-6 inhibitor), and inebilizumab (a B-cell depleting agent) were approved for adult use in 2019. These drugs, along with rituximab, are often used off-label in the pediatric population.

In conclusion, APS is a syndrome caused by lesions of the dorsal caudal medulla that produces intractable nausea, vomiting and hiccups. APS is a core clinical feature of NMOSD and often precedes the development of optic neuritis and transverse myelitis. Patients whose first presentation of NMOSD is APS are frequently misdiagnosed with GI disorders on initial presentation, leading to delays in diagnosis and poor control of symptoms. Clues that chronic nausea and vomiting may be caused by APS include a negative GI workup result, a poor response to antiemetics, concomitant intractable hiccups, the presence of other neurologic signs or symptoms, or a rapid response to immunotherapy. In these contexts, physicians should maintain a high index of suspicion for APS because timely recognition can allow for the initiation of chronic immunomodulatory therapy and delay the accrual of attack-related disability.

Glossary

APS

area postrema syndrome

AQP4

aquaporin 4

CNS

central nervous system

ED

emergency department

GI

gastrointestinal

IgG

Immunoglobulin G

MOG

myelin oligodendrocyte glycoprotein

MS

multiple sclerosis

NMOSD

neuromyelitis optica spectrum disorder