Nausea and vomiting are one of the cardinal symptoms of migraine. In a clinic-based study from Canada, nausea was present in over 90 % of the patients visiting headache specialists [15]. In a population-based study of about 6500 individuals with episodic migraine, half reported nausea more than half the times and another 29 % reported less than half the times they experienced nausea with headaches [16]. Nausea also appears to be more common in females compared with males [16]. Nausea in patients with migraine seems to have a global impact as it is associated with more headache symptoms, occupational disability, medical leaves, and self-reported financial burden [3, 16]. In addition, nausea symptoms are potential barrier to effective migraine treatment. In 2010, National Headache Foundation Survey, 4 in 10 patients with migraine endorses delaying or avoiding their oral medication because of migraine-associated nausea and vomiting [16]. Thus, nausea and vomiting independently contribute to migraine-related disability and represents more severe subset of patients with migraine. Patients with episodic migraine and frequent headache-related nausea have a twofold risk of developing into patients with chronic migraine [17].

Using a PET-based study, Maniyar et al. have shown nausea in migraine is associated with activation in rostral dorsal medullary areas such as nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus nerve and nucleus ambiguus along with periaqueductal gray matter which are all known to be involved in nausea pathway [18]. The study showed that migraine in nausea is not related to pain and trigeminal activation [18, 19].

Treatment of migraine itself can relieve nausea and vomiting in several cases. In addition, trying to avoid individual triggers for nausea and vomiting in some patients may also be recommended. Oral medications are less effective once the migraine event has started because of decrease in gastrointestinal motility and subsequent drug bioavailability [20]. In addition, oral triptans contribute to the development of nausea among migraine patients who are nausea-free before treatment [20]. In patients with nausea, oral drugs may be effective. Nevertheless, if the patients are vomiting, the treatment should be administered parenterally, intranasally, or rectally to guarantee their absorption. When needed, the treatment with tripatans and/or analgesics can be combined with antiemetics such as chlorpromazine, metoclopramide, domperidone, or promethazine [21]. Drugs such as metoclopramide are also prokinetic and thus could also improve migraine-associated gastric stasis [21]. In randomized controlled trials, intravenous chlorpromazine (1 mg/Kg) and droperidol (2.75 mg, 5.5 mg, and 8.25 mg) have all been shown superior to placebo in providing headache relief at the end of 1–2 h in patients with acute attacks of migraine [22–24]. Similar results have been shown for other antiemetics such as metocloperamide which has been shown to superior to placebo in reducing headache pain and requiring rescue drugs in treatment of acute migraine attack [25].

About 25 % of the patients with Parkinson’s disease have nausea or vomiting with half of them complaining of severe symptoms [26]. In Parkinson’s disease, the stimulus for nausea and vomiting could be central or peripheral in origin. Studies have consistently reported delayed gastric emptying in 55–100 % of patients with Parkinson’s disease [27–30]. There is some evidence that it might be more impaired in patients with familial Parkinson’s disease than sporadic Parkinson’s disease [28]. While most of the studies did not find a correlation between disease severity and gastric emptying time, one study did [27, 29, 31, 32]. However, the inability of patients with very severe disease to undergo scintigraphy may have limited this evaluation [30]. Gastric emptying rate has not been shown to correlate with duration of Parkinson’s disease or gastrointestinal symptoms [30]. Delayed gastric emptying has therapeutic implications as it has been shown to have effect on drug delivery and possibly response fluctuations [30, 33–35]. Majority of patients with Parkinson’s disease have high frequency fasting gastric dysrhythmias on electrogastrography, a finding that has been shown to be associated with nausea and vomiting [36–38]. The delayed gastric emptying and gastric dysrhythmias in patients with Parkinson’s disease is likely because of involvement of both enteric as well as central nervous system. Lewy body deposition has been described not only in myenteric and submucosal plexus of stomach but also central structures of autonomic nervous system including dorsal motor nucleus of vagus and could be contributing to these findings [30].

In addition to delayed gastric emptying and gastric dysrhythmias in patients with Parkinson’s disease, nausea could also result from pharmacological treatment of Parkinson’s disease [39]. Nausea is a very common side effect of dopaminergic therapy which generally occurs immediately after initiating therapy [39]. Nausea occurs in about 15–35 % of the patients starting dopaminergic treatment [39, 40]. Nausea occurs because of agonistic effect of these drugs on dopamine receptors in the gut as well as area postrema. Dopa decarboxylase inhibitors such as carbidopa prevent peripheral conversion of levodopa to dopamine and could improve levodopa-induced nausea and vomiting [41]. Carbidopa is, however, ineffective in mitigating the nausea induced by dopamine agonists. Domperidone, a peripheral D2 receptor antagonist that does not cross blood brain barrier (BBB), has been shown to reduce nausea from dopaminergic medications [42, 43]. In a randomized controlled trial of 182 patients with Parkinson’s disease, trimethobenzamide has been shown to reduce nausea or vomiting during the first 8 weeks of apomorphine therapy without worsening Parkinsonism features [44]. Other antiemetics such as metocloperamide, promethazine, and prochlorperazine can worsen the Parkinson’s disease and thus should be avoided [30].

Vomiting has been reported in up to 15 % of all stroke patients [45]. It is more often seen in hemorrhagic stroke patients than patients with ischemic stroke with up to 24 % of patients with intracerebral hemorrhage complaining of vomiting as compared to 9 % of patients with ischemic stroke [45, 46]. The frequency of stroke is even higher (up to 1.5 times) in patients with subarachnoid hemorrhage as compared to intracerebral hemorrhage [45]. In a study combining results of 19 prospective studies, presence of vomiting at the time of presentation increased the probability of having hemorrhagic stroke by threefold [46]. In addition, patients with vomiting at the time of presentation of stroke (ischemic or hemorrhagic) have been shown to have fivefold increased risk of death when compared to those who did not [45]. Cases of cyclic vomiting syndrome after a stroke have also been reported [47].

As the vertebral, basilar, and posterior cerebral arteries supply blood to brainstem, nausea and vomiting are also one of the fairly common symptoms of posterior circulation stroke. At a tertiary care center, 27 % of about 400 consecutive patients with posterior circulation transient ischemic attack/stroke complained of nausea and vomiting [48]. In these cases, diplopia, dysarthria, dysphagia, vertigo, drowsiness, and various other features such as cranial nerve deficits usually coexist at the presentation of nausea and vomiting and aid in diagnosis [49].

Although nausea and vomiting occur commonly in patients with hemorrhagic or ischemic stroke, their pathophysiology is not very well understood. Cerebral edema after stroke leading to increased intracranial pressure and meningeal stimulation could be contributing to the symptoms of nausea and vomiting in these patients [50, 51].

Neuromyelitis optica (NMO) is a central nervous system demyelinating autoimmune disorder characterized by relapsing attacks that are characterized by involvement of optic nerves, spinal cord, and periventricular brain regions. Medullary involvement of NMO is characterized by intractable nausea, vomiting, and hiccups which often precede NMO relapses but can also occur as isolated clinical manifestation of the disease [52, 53]. Intractable nausea and vomiting are present in 16–43 % of the patients with NMO [52–54]. Intractable nausea and vomiting are the initial presenting in about 13 % patients with NMO [55]. In such cases, nausea and vomiting are often evaluated by gastroenterologists and neurological evaluation is delayed or not pursued [53, 56].

NMO is likely an organ-specific autoimmune disorder mediated by IgG antibodies targeting water channel aquaporin (AQP-4) of central nervous system [54, 57]. These autoantibodies penetrate the CNS through endothelial transcytosis or at area of relative blood brain barrier (BBB) permeability or injury and bind to aquaporin channels on the surface of astrocytes [58]. Area postrema is a key structure involved in the central pathway of vomiting and consists of loose tissue containing glia and neurons, has a thin ependymal cover, and is penetrated by convoluted capillaries that lack tight epithelial junctions forming relatively permeable BBB [59, 60]. In addition, it is one of the most vascularized brain regions. There is also slowing of blood in this region due to specialized pericapillary pool of interstitial fluid [56, 60]. Furthermore, AQP-4 water channels are present in abundance in area postrema region. All these factors collectively make area postrema the preferential target of AQP-4 IgG antibodies in NMO [56]. Histopathological studies have demonstrated selective AQP-4 loss in area postrema accompanied by tissue rarefaction, inflammation, variable complement deposition, and nonlytic alteration in astrocytes [56]. The involvement of area postrema has also been confirmed on MRI in patients with NMO presenting with intractable nausea and vomiting [53]. Studies have shown 16-fold increased risk of having nausea, vomiting in NMO patients with involvement of area postrema as compared to those who did not, emphasizing involvement of area postrema as the basis of intractable nausea and vomiting in this debilitating disease [56].

Early detection of IgG AQP-4 antibodies is the key to diagnosis and could allow the patients to receive immunosuppressive therapies, at times, before the onset of optic neuritis or transverse myelitis [55]. MRI of brain could also aid in the diagnosis by showing involvement of periventricular structures.

The first-line treatment of acute attack is intravenous corticosteroids for five consecutive days [58]. Plasmapheresis is the second-line treatment if intravenous corticosteroid fail. Intravenous immunoglobulins have also been investigated and have shown some efficacy. Several immunosuppressive therapies including azathioprine, mycophenolate moefitil, rituximab, mitoxantrone, and methotrexate have been used successfully for maintenance therapy for attack prevention [58]. Most of the patients with intractable vomiting require inpatient hospitalization for hydration and intravenous antiemetic therapy.

Nausea and vomiting are very uncommon in other demyelinating diseases such as multiple sclerosis. However, case reports of nausea and vomiting as primary presenting manifestation of multiple sclerosis has been reported [61, 62].

Nausea and vomiting in patients with cancer are generally due to chemotherapy and radiation. In addition to these, there are gastrointestinal (bowel obstruction, peritoneal carcinomatosis, severe constipation), metabolic (hypercalcemia), and psychiatric (anxiety related) causes of nausea and vomiting [63]. In patients with advanced oncological disease, nausea and vomiting could also be related to central nervous system especially brain metastasis [63]. Brain metastasis occurs in 9–17 % of cancer patients with lung, breast and melanoma being the commonest causes [64]. In addition to increasing intracranial pressure by mass effect, brain and leptomeningeal metastasis can also raise intracranial pressure by causing obstructive hydrocephalus and hemorrhage in metastases. Furthermore, direct effect on structures involved in nausea/vomiting pathways leading to vomiting without causing raised intracranial pressure or hydrocephalus has also been reported [65]. The treatment is often directed to brain metastasis in the form of surgery and/or whole brain radiation, stereotactic radiosurgery alone or in combination [66]. There is some evidence that targeted and immune therapies are useful in melanoma and renal cancers with brain metastases [67, 68]. Symptomatic patients with brain metastases also benefit from dexamethasone 4–8 mg/day in divided doses [66]. Higher doses along with emergent surgery should be considered in patients with hydrocephalus and impending brain herniation [67].

Vomiting is rarely the main manifestation of epileptic episode [69]. In a study of 900 adults and children with epilepsy, Panayiotopoulos et al. reported that only 24 patients had vomiting during ictal episode [70]. In the study, all 24 patients were prepubertal children with a similar clinical pattern of nocturnal partial seizures. International League Against Epilepsy has recently identified a form of early onset benign childhood epilepsy, Panayiotopoulos syndrome, characterized by tonic eye deviation and ictal vomiting [71–73]. These seizures are often accompanied by autonomic symptoms such as pupillary changes, pallor/flushing, alterations in heart rate, breathing irregularities and temperature instability [74]. In a study by Kivity et al., less than 50 % of the patients with Panayiotopoulos syndrome had ictal vomiting and those with ictal vomiting had significantly higher frequency of prolonged vomiting than those who did not [72]. In addition, ictal vomiting has also been described in adults with complex partial seizures of temporal lobe origin [75]. In cases of temporal lobe seizures, it was thought to be localizing to right or nondominant lobe temporal lobe seizures [76, 77]. However, several cases of ictal vomiting from dominant temporal lobe seizures have also been reported [69, 78, 79].

Studies have shown that mesial and anterior temporal lobe structures had most active interictal epileptiform discharges and ictal vomiting was associated with spread of electroencephalographic seizure pattern to more lateral and superior regions of temporal lobe [77]. Sometimes, interictal electroencephalogram can be normal in these patients and an ictal electroencephalogram might be needed for diagnosis [69]. One study showed that although the seizure onset zone was localized in the temporomesial structures, but the occurrence of ictal vomiting correlated in time with a discharge affecting exclusively the anterior part of both insular lobes [79]. These findings may point to activation of insular or limbic circuits whose descending influence on vomiting center or chemoreceptor trigger zone would initiate the vomiting reflex [77, 79].

In children with Panayiotopoulos syndrome, a large proportion of patients are not routinely treated with antiepileptic drugs. Low seizure frequency and severity, parental and child preference, and nocturnal seizure predominance were shown to be the most important factors influencing a policy of no treatment [74]. The evidence base for treatment choice for this syndrome is acknowledged to be poor, with some studies suggesting that carbamazepine and sodium valproate are “possibly” effective, and levetiracetam, oxcarbamazepine, gabapentin, and sulthiame “potentially” effective as initial monotherapy [74]. In adult patients with temporal lobe seizures, various antieplieptic are used alone or in combination [69]. Some cases are difficult to control with antiepileptics alone and might require surgical intervention [75].

Pseudotumor cerebri refers to symptomatic intracranial hypertension in patients without intracranial mass lesion, ventriculomegaly, or underlying central nervous system infection or malignancy [80]. Idiopathic intracranial hypertension (IIH) is the primary form of pseudotumor cerebri that most commonly occurs in obese adolescent or adult females but can occur in males also. Secondary pseudotumor cerebri may be clinically indistinguishable from IIH, but results from an identified medical conditions (polycystic ovarian syndrome, Addison disease), medication toxicity (Vitamin A and derivatives, antibiotics especially tetracyclines, hormones), venous abnormality (cerebral venous sinus thrombosis, superior vena cava syndrome, etc.), or decreased absorption of CSF due to damage to the arachnoid granulations (postbacterial meningitis or subarachnoid hemorrhage) leading to elevated intracranial pressure [80].

Headache is the most common symptom of pseudotumor cerebri occurring in up to 90 % of the patients with visual loss due to papilledema being the most feared complication [81, 82]. However, dizziness, tinnitus, nausea, and vomiting are also associated with IIH and can be incapacitating for some patients. The pathophysiology of these symptoms are not clearly understood but are thought to be due to compressive neuropathy of vestibule-cochlear nerve from intracranial pressure [83].

Diagnosis of pseudotumor cerebri is based on papilledema, normal neurological examination (except cranial nerve findings), neuroimaging consistent with the diagnosis, elevated lumbar puncture opening pressures, and normal CSF composition [80]. Its treatment includes weight loss in obese patients and acetazolamide as medical therapy. In certain cases, cerebral transverse sinus stenting, repeated lumbar puncture, and CSF shunting procedures are also considered [84].