Sandifer Syndrome

Sandifer syndrome involves spasmodic torsional dystonia with arching of the back and rigid opisthotonic posturing, mainly affecting the neck, back, and upper extremities, associated with symptomatic gastroesophageal reflux, esophagitis, or the presence of hiatal hernia.[1, 2]

Pediatric neurologists may be the first to see patients with Sandifer syndrome because the primary care provider and the parents may believe that the spasms represent seizures. Pediatric emergency department physicians and gastroenterologists see patients with this complex with some frequency.

Although case reports of Sandifer syndrome are available, the syndrome is underrecognized. Delays in diagnosis are due to atypical presentations or cases in which the diagnosis is not part of the differential.[3, 4, 5, 6, 7]

The true pathophysiologic mechanisms of Sandifer syndrome remain unclear.

Dysfunction of the lower esophagus with resultant acidic reflux is thought to be the most common precipitating factor, with the episodes of posturing coinciding temporally with recent feedings. Although gastroesophageal reflux is common and indeed physiologic in infants, gastroesophageal reflux disease (ie, concerning symptoms or complications associated with the reflux) is much less common.[8]

Concerning symptoms may include evidence of pain (presumed to be the cause of the posturing), irritability, poor weight gain, sleep disturbance, and respiratory symptoms. Typically, empiric treatment for gastroesophageal reflux disease alleviates symptoms of Sandifer syndrome.  

Hiatal hernia may be associated with Sandifer syndrome, particularly in children older than infancy, and presumably exacerbates the gastroesophageal reflux.

International data

The incidence of Sandifer syndrome is unknown, although some evidence suggests that in clinical practice it occurs in fewer than 1% of children with gastroesophageal reflux.[3]

Race-, sex-, and age-related demographics

Race does not seem to influence incidence, and no sex predilection is recognized.

Typically, Sandifer syndrome is observed from infancy to early childhood. Peak prevalence is in individuals younger than 24 months. Children with mental impairment or spasticity may experience Sandifer syndrome into adolescence.

Morbidity/mortality

Morbidity consists of the discomfort associated with Sandifer syndrome.[9]  Infants may lose weight if persistent or severe gastroesophageal reflux disease (GERD) is present. Associated morbidities may also include the presence of a hiatal hernia and esophagitis.

Typically, Sandifer syndrome is not life-threatening. Many patients with the condition eventually outgrow the spasms in later childhood.

Complications

Sandifer syndrome per se is not associated with specific complications. However, misdiagnosis (eg, as a neurologic problem) may result in a significant delay in the diagnosis of associated GERD and timely intervention.[10]

Sandifer syndrome is most commonly mistaken for seizures.[3, 4, 6, 11] The infant or child typically appears to have an alteration in mental status associated with the tonic posturing.

A relationship with feeding suggests the diagnosis of Sandifer syndrome, which commonly occurs after feeding.

Posturing is typically brief, temporally associated with feeding, paroxysmal, and absent during sleep. The child may have a sudden deviation of the head and neck to one side and the legs to the opposite side with a stretched-out appearance. Typically, the back is arched posteriorly with hyperextension of the spine, and elbows may be flexed and held posteriorly with hyperextended hips. Torticollis may be present.[3, 6, 11, 12]

Although the intermittent stiff tonic posture and periods of crying and apparent discomfort may suggest seizures, in many cases the rhythmic clonic component, which may be present in seizures, is not described.

Various stiff, bizarre postures can be observed, with the following features noted:

• Typically, the duration of the posture is 1-3 minutes.
• This brief, paroxysmal pattern of posturing accounts for the fact that the movement observed in Sandifer syndrome may be mistaken for seizures.
• During the posture, the infant may become very quiet or, less commonly, become very fussy. Fussiness and evident discomfort are most commonly observed as the posture abates
• If a significant volume of gastroesophageal reflux is observed, even without actual vomitus, some infants and children may exhibit evidence of respiratory tract irritation as well, including cough, wheezing, and stridor, depending on the degree and volume of reflux. ^[13]

In children with Sandifer syndrome without mental impairment, the physical examination findings are normal. Children with Sandifer syndrome with mental impairment may have evidence of spasticity and may receive a diagnosis of cerebral palsy.[14]

Sandifer syndrome in infants is most commonly associated with normal physical examination findings. In older children, the syndrome may be associated with mental impairment or anatomic abnormalities of the gastrointestinal tract, such as hiatal hernia.

In infants with significant gastroesophageal reflux disease or unsuspected milk protein allergy, the physical examination may reveal evidence of poor nutrition, poor weight gain, and occult blood on fecal guaiac testing.

Sandifer syndrome is a clinical diagnosis, and most infants have normal physical examination findings. Thus, empiric interventions and therapy are warranted in the absence of clinically concerning features, such as the following:

• Abnormal results of a baseline neurologic examination
• Clinical or historical features that suggest an underlying metabolic or genetic disorder
• Concerns about nutritional status
• Respiratory complications
• Known seizure disorder

A stool guaiac test may be useful; occult gastrointestinal (GI) bleeding may occur with gastroesophageal reflux disease (GERD) and esophagitis or with milk protein allergy, both of which may be causative.

If there are clinical concerns about nutritional or metabolic status, then screening tests such as basic chemistry panels, blood cell counts, or urinalysis may be useful.

Upper GI imaging (eg, fluoroscopic imaging of swallowed barium) is not recommended as a means of diagnosing gastroesophageal reflux or GERD; the study is neither sufficiently sensitive nor specific. Furthermore, the presence or degree of reflux does not correlate with the severity of possible esophageal mucosal inflammation. Upper GI imaging may be useful to screen out other anatomic abnormalities, such as hiatal hernia if that is a clinical concern, for example, in an older child.

Gastroesophageal scintigraphy is not recommended in the routine evaluation of pediatric gastroesophageal reflux.

Cranial magnetic resonance imaging may be helpful in defining the nature of neurologic deficits in children with mental impairment or in ruling out concomitant cranial anatomic abnormalities.

Video-electroencephalography monitoring can help differentiate seizures from posturing related to reflux and can be combined with a pH probe/multichannel intraluminal impedance (MII) study to demonstrate the nature of the episodes and any correlation with findings of reflux.

The traditional use of a 24-hour pH probe to document the acidity (pH < 4) of reflux and its duration is no longer considered a primary modality in defining or characterizing the severity of GERD. MII testing, which measures the passage—both anterograde and retrograde—of air, fluids, and solids in the esophagus, is another modality used to correlate symptoms and reflux. Clinical practice guidelines recommend the use of combined MII and pH testing on a single probe to enhance the quality and usefulness of each.[8]

Endoscopy with performance of esophageal biopsy is the most sensitive way to diagnose esophageal inflammation due to reflux and may be useful to rule out other conditions that can cause esophageal inflammation, which could mimic GERD. In general, an invasive procedure requiring sedation such as endoscopy should be limited to patients with unusual presentations and to those who are not responsive to more conservative tests and the usual interventions and therapies.

There are no histologic findings that define Sandifer syndrome. If endoscopy with esophageal biopsy is performed, the results may confirm conditions ranging from mucosal inflammation to erosive esophagitis that can cause Sandifer syndrome.

Most cases of Sandifer syndrome resolve with time and development, within the first 24 months. Initial interventions should be directed at the following lifestyle changes:

• Modification of or attention to feeding habits
• Adjustment of feeds (whether breast milk or formula)
• Exclusionary diets
• Positioning

Typical medications directed at gastroesophageal reflux disease (GERD) include acid suppressants (H2 receptor antagonists, proton pump inhibitors), buffers (antacids), and prokinetic agents. These medications are used to treat GERD in older children and adults. There are very limited data about their usefulness in infants under age 12 months. Those studies that have been done show mixed results with respect to the efficacy of these pharmacologic interventions versus their recognized adverse effects and cost.[16, 17, 18, 19, 20, 21]

Sandifer syndrome generally does not require treatment and typically resolves in the first 12-24 months of life. During this period, nutrition is gradually less dependent on volumes of fluid, and the lower esophageal sphincter function improves unless the spasms result from gastroesophageal disease that is severe enough to interfere with growth and feeding. In the latter case, therapy should be directed toward the specific cause (see Pediatric Gastroesophageal Reflux for more detail). The American Gastroenterological Association has issued guidelines for the management of GERD.[22]

The primary aim of medical care is to identify Sandifer syndrome. This can be accomplished most often by soliciting a careful history of the times of day the spasms occur and their association with feeding. If recognizing the complex is difficult, then video-electroencephalography monitoring or additional evaluation for possible GERD may be of value (eg, pH probe/multichannel intraluminal impedance study).

Often, parent education and explanation regarding the nature of the spasms are all that is required in the treatment of Sandifer syndrome. If the patient has pathologic gastroesophageal reflux or complications from gastroesophageal reflux such as cough, poor growth, or guaiac-positive stools, then consideration of milk protein allergy or intervention for GERD may be indicated.

In patients with severe, confirmed gastroesophageal disease that is unresponsive to medical therapy and conservative interventions and that interferes with growth and development, some evidence suggests that fundoplication may alleviate symptoms.[3] See the image below.

Diagram illustrating the Nissen fundoplication. Note how the stomach is wrapped around the esophagus (360º wrap).

Primary care pediatricians should consider and be able to recognize the symptoms of Sandifer syndrome. In the absence of other concerning findings on the history or physical examination, it is appropriate for the primary care pediatrician to initiate dietary and other lifestyle interventions.

In cases that are refractory to conservative interventions or that raise suspicion of other possible gastrointestinal pathology, referral to a pediatric gastroenterologist is appropriate.

If any doubt surrounds the nature of the seizurelike activity or if the child has underlying neurologic impairment, a consultation with a pediatric neurologist may be beneficial.

Dietary interventions typically include sequential trials of the following: 

• Feeding modifications, such as smaller volume, more frequent feeding, and avoiding overfeeding.
• Use of thickened feeds, including rice or oat cereals or other types of thickeners (see Pediatric Gastroesophageal Reflux for more detail).
• Use of extensively hydrolyzed protein- or amino-acid–based formula with or without thickening.
• For breast-fed infants, modification of maternal diet to exclude cow's milk and eggs. ^[8]

Other lifestyle interventions include avoidance of second-hand tobacco smoke exposure, maintaining the infant in a semi-upright position for 30 minutes after feeding, and avoiding seated or supine positioning during the immediate period after feeding.[8, 20, 21, 23]

The therapeutic response to the treatment of gastroesophageal reflux disease (GERD) may take several weeks. If treatment is successful, the frequency of posturing and apparent distress will decrease.

Class Summary

These agents are used to augment cholinergic activity. As such, they can improve contractility of the lower esophagus, increase lower esophageal sphincter pressure, and augment the rate of gastric emptying. However, these agents have a limited role in this age group as the risk of adverse side effects generally outweighs benefit. Current guidelines do not support the routine use of prokinetic agents for the treatment of GERD in infants or older children.[8, 20] Use of PPIs should be considered only in specific situations, with thorough consideration of risks and benefit.

Metoclopramide (Reglan)

Dopaminergic antagonist that works by increasing LES tone and gastric emptying. Stimulates muscular activity, leading to decrease in reflux.

Class Summary

These agents have traditionally been used as a diagnostic tool, providing symptomatic relief in infants. However, although they may confer short-term relief, they are not recommended for long-term use due to the risk of associated aluminum toxicity,[24, 25, 26]  calcium toxicity such as milk-alkali syndrome (hypercalcemia, alkalosis, renal failure),[23]  and magnesium toxicity.[27]  They are NOT currently recommended for the treatment of GERD or esophagitis in infants and children.[17, 23]

Aluminum hydroxide (ALternaGEL, Amphojel)

Increases gastric pH above 4 and inhibits proteolytic activity of pepsin, reducing acid indigestion. Antacids can initially be used in mild cases. No effect on frequency of reflux but decreases its acidity.

Class Summary

Like antacids, these agents do not reduce the frequency of reflux, but they are very effective in decreasing the amount of acid in the refluxate through inhibition of acid production by blocking the histamine H2 receptors on gastric parietal cells. All are equipotent when used in equivalent doses. Long- term use is limited by the development of tachyphylaxis  or tolerance. These medications are very useful for short term trial of acid suppression.

Ranitidine (Zantac)

Inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

Competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Nizatidine (Axid)

Nizatidine is approved by the FDA for use in adolescents aged 12-18 y. Off-label use in children younger than 12 y has been described.

Class Summary

Proton pump inhibitors (PPIs) decrease acid secretion by irreversibly binding to and inhibiting the H+-K+-ATPase pump on the gastric parietal cell surface. They are more effective at increasing gastric pH, and for a longer duration, compared with H2 receptor antagonists (H2RA). Additionally, they do not cause the tolerance seen after several weeks use of the H2RAs. As a result, PPIs contribute to more rapid healing of erosive esophagitis.[28] There is mixed evidence as to their efficacy in reducing irritability in infants.[18, 29]  Concerns exist regarding overuse and over prescribing of PPIs, and the long-term adverse effects (eg, increased in respiratory infections in infants, headache, nausea, diarrhea and constipation in older children and adults).[8, 23]  

Omeprazole, lansoprazole, pantoprazole and esomeprazole have all been studied in infants and young children. Currently, the only PPI approved by the FDA for use in infants aged 1-12 months is esomeprazole.

Omeprazole (Prilosec)

Decreases gastric acid secretion by inhibiting the parietal cell H+-K+-ATP pump.

Lansoprazole (Prevacid, Prevacid 24HR, Prevacid Solu Tab)

Suppresses gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system (ie, proton pump) at the secretory surface of the gastric parietal cell. It blocks the final step of acid production. The effect is dose-related and inhibits both basal and stimulated gastric acid secretion, thus increasing gastric pH.

Esomeprazole magnesium (Nexium)

S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+-K+-ATPase enzyme system at secretory surface of gastric parietal cells.