Area postrema syndrome: Intractable hiccups and vomiting as a result of neuromyelitis Optica Spectrum disorder

Abstract

A 31 year old woman was referred to the medical team for further investigation of intractable hiccups and vomiting. Initial investigations including blood tests, endoscopy and CT imaging did not identify any cause of symptoms. Following multidisciplinary team review, serial MRI Head imaging was arranged, which revealed progressive posterior fossa signal abnormality with involvement of the area postrema. In combination with a positive serum Aquaporin-4 antibody result, this helped establish a diagnosis of Neuromyelitis Optica Spectrum Disorder (NMOSD). Treatment included high dose steroids, plasma exchange and immunomodulatory therapy, and led to a marked improvement in symptoms. This case highlights the importance of utilising specialty team input and broadening lines of investigation, when managing patients with intractable hiccups and vomiting in whom an initial workup has not established a clear diagnosis. While NMOSD is rare, early identification can inform treatment strategies that may lead to a significant improvement in clinical outcome.

Summary

The investigation of nausea and vomiting can be challenging, with wide ranging possible underlying aetiologies necessitating a clinically guided diagnostic strategy.

We present a case of a patient with area postrema syndrome, in which intractable nausea and vomiting was a predominant presenting feature of Neuromyelitis Optica Spectrum Disorder (NMOSD).

Case report

A 31 year old woman was admitted under the care of the acute medical team, with a one month history of intractable hiccups and vomiting. She was of Black African heritage, previously fit and well, with no significant past medical history. She was not taking any regular medications, did not smoke or drink alcohol and had no history of illicit drug use.

The patient had attended the Emergency Department (ED) on four previous occasions but in the context of unremarkable examination findings and blood tests, had been sent home each time with advice on supportive management. On her fifth presentation to the Emergency Department, she was admitted for further workup.

The patient was suffering from debilitating hiccups and vomiting up to 10 times a day. She also reported unsteadiness her feet, visual blurring and a mild headache. She denied any infective symptoms and was not experiencing fevers. There was no history of trauma.

On examination her pulse was 73 beats per minute with a blood pressure of 131/83 mmHg. She was afebrile. Whilst a normal neurological examination had been documented on each of her four previous ED attendances, positive signs were identified at the time of her admission. There was evidence of horizontal torsional nystagmus to the right, left upper limb dysmetria and an ataxic gait. No other focal neurology was evident. There were no signs of meningism and no rash. Blood tests demonstrated a mildly elevated ESR of 40, though CRP was 1. Lumbar puncture was unremarkable. A CT Head did not identify any gross central pathology.

Following multi-disciplinary team input, MRI Head imaging was arranged, which revealed subtle FLAIR hyperintensity in relation to the right superior cerebellar peduncle and periaqueductal grey matter [Figure 1]. Interval MRI imaging then demonstrated a progression of the posterior fossa signal abnormality and new involvement of the area postrema, a clear structural correlate for persistent hiccups, nausea and vomiting. Further targeted blood tests confirmed the presence of serum Aquaporin-4 antibodies, and helped establish the diagnosis of Neuromyelitis Optica Spectrum Disorder (NMOSD).

Figure 1.

MRI T2/FLAIR sequencing demonstrating hyperintensity in the dorsal medulla and floor of the fourth ventricle in the region of the area postrema. Yellow circles – area postrema. Green ovals – abnormal FLAIR signal within superior cerebellar peduncles.

The patient was started on a 3 day course of pulsed methylprednisolone 1 g once daily, followed by a weaning course of oral prednisolone starting at 60 mg once daily. The patient then underwent 5 sessions of plasma exchange. Azathioprine was commenced at a dose of 25 mg once daily (TPMT 22), with the intention of uptitrating this to a maintenance dose of 75 mg once daily (∼1 mg / kg). Gabapentin 300 mg TDS was given to help treat the nystagmus.

These interventions led to a significant improvement in the patient's symptoms. The hiccups resolved completely. The nausea and vomiting also settled, and the patient was able to eat and drink without limitation. The patient did however report ongoing unsteadiness on her feet, and community neurophysiotherapy was organised on discharge. The total inpatient stay was one month.

The patient was reviewed in a specialist Neuro-Inflammatory clinic 3 months after discharge and at this point had made a good but incomplete recovery. Whilst the nausea, vomiting and hiccups remained largely abated, the patient did report arthralgia and dizziness. Further interval MRI imaging 6 months post discharge demonstrated resolution of the signal abnormality in relation to the floor of the fourth ventricle and dorsal medulla. Ongoing Neurology outpatient follow-up is in place, and Rituximab may be considered if the patient develops any signs of breakthrough disease.

Discussion

Vomiting is defined as the forceful oral expulsion of gastric contents associated with contraction of the abdominal and chest wall musculature, whilst nausea refers to the unpleasant sensation of the imminent need to vomit. ¹ Nausea and vomiting are common presenting complaints, ² and responsible for significant disease morbidity, both on an individual basis and on a wider socioeconomic scale. ³

Investigation of nausea and vomiting is largely determined by the individual clinician, with no defined assessment algorithm in common usage. In the context of the wide-ranging possible aetiologies (infective, pharmacological, metabolic, obstructive) and broad panel of potential investigations (blood tests, radiology, endoscopy), less commonly encountered pathology can be missed, as highlighted in this case.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare neuro-inflammatory demyelinating disorder, with an estimated prevalence of 0.52-4.4 per 100 000. ⁴ In a proportion of patients it presents with intractable vomiting.^5,6,7,8

Whilst traditionally considered a variant of Multiple Sclerosis (MS), it is now recognised as a distinct clinical entity. The presence of the highly specific Aquaporin-4 (AQP4)IgG serum antibody is often helpful in differentiating the two conditions. ⁹

International Consensus diagnostic criteria, ⁶ published in 2015, categorise cases of NMOSD into those that are AQP4-IgG positive and those where AQP4-IgG status is negative or unknown. They identify 6 core clinical characteristics:

Optic neuritis

Acute Myelitis

Area postrema syndrome (APS): episode of otherwise unexplained hiccups or nausea and vomiting

Acute brainstem syndrome

Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions

Symptomatic cerebral syndrome with NMOSD-typical brain lesions

Cases with positive AQP4-IgG require at least 1 positive core clinical characteristic, as well as for alternative diagnoses to be excluded. However, criteria for NMOSD without AQP4-IgG are stricter, requiring at least 2 core clinical characteristics (where at least one is optic neuritis, acute myelitis with Longitudinally Extensive Transverse Myelitis (LETM) or area postrema syndrome), dissemination in space, and fulfilment of additional MRI requirements, alongside exclusion of alternative diagnoses. ⁶

The area postrema is a region of the dorsal medulla, located at the base of the fourth ventricle, which acts as an emetic reflex centre and is involved in the regulation of fluid balance, osmoregulation and immunomodulation. Area Postrema Syndrome (APS) refers to the symptoms of hiccups, nausea and vomiting, related to inflammation within this this region^7,8 Symptoms may be prolonged, with vomiting lasting a median of 4 weeks in one case series. ⁵ The frequency of isolated APS at onset of NMOSD was 7.1% in one review of UK patients, ⁷ Between 16–43% of patients suffer from APS at some point during their NMOSD illness.^5,7,8

Whilst the core clinical characteristics of NMOSD are clearly defined, the relative rarity of the condition combined with the non-specificity of typical APS findings can make diagnosis challenging.

Effective multidisciplinary team input is of paramount importance. In the discussed case, the patient received input from the emergency department, acute medicine, gastroenterology, neurology and radiology teams, across both district general and tertiary hospital sites. It is therefore important that clinicians working in all of these settings are familiar with NMOSD. Lack of cross-specialty awareness of the condition may result in incorrect diagnosis ⁷ and delays in treatment initiation.^5,7,10

Variability in the clinical course of NMOSD can also pose challenges. In the presented case, no focal neurology beyond hiccups and vomiting had been identified on the patient's initial four ED attendances. This may well be consistent with the patient having developed features of APS prior to the other neurological manifestations associated with NMOSD. It is in this subset of patients that there is a very real risk of misdiagnosing a functional vomiting disorder.^7,10 Modern therapy can alter disease progression and therefore timely diagnosis is key. ¹⁰

Treatment of acute NMOSD is with high dose steroids (typically 1 g methylprednisolone for 5 days), and then with plasma exchange if there is insufficient improvement, though there are some data that early treatment with plasma exchange may be beneficial.^10,11,12

Learning points

• Nausea and vomiting, whilst a common presentation, can occur secondary to rare pathology such as NMOSD, and this needs to be considered and excluded where relevant

• Effective multidisciplinary team input is essential when investigating cases of nausea and vomiting

• When symptoms are intractable, persistent or do not improve with standard treatments then it may be helpful to revisit the initial diagnosis, and consider broadened lines of investigation

• MRI imaging of the Central Nervous System should be considered in all cases of intractable nausea and vomiting in which CT Head imaging is normal though central pathology is still suspected

• Early diagnosis and treatment of NMOSD is crucial in reducing disability and improving long term outcomes.