Crying and agitation for no apparent reason in children with severe neurologic impairment is a common and frustrating problem for parents and providers alike.1 It is not unusual for families to make frequent trips to their primary care provider or to the emergency department (ED) for this problem. The patients referred to in this article are nonverbal, nonambulatory, and dependent on others for care. Such patients are unable to provide obvious clues as to what is making them uncomfortable, and their episodes of persistent crying or screaming cause distress to their family.
A methodical approach is helpful in dealing with this problem, yet sometimes the cause is not apparent, even after a thorough search. It is helpful to explain to parents and caretakers that the cause of the distress may take some time to figure out, and that diagnosis is often difficult. However, in most cases, a satisfactory treatment can be found.
Initial approach and differential diagnosis
The first step, as with any medical complaint, is to obtain a thorough history, followed by a physical examination looking for potential causes of pain. How long has the pain or irritability been present? Are there any triggers or precipitating events? Does anything make the crying better or worse? Was the onset associated with any changes at home, trauma, medication regimen, or other significant changes in care or treatment? Are there any signs of an acute illness or infection?
Consider the following list of problems while performing a history and physical exam, and deciding on laboratory tests. The differential diagnosis discussed below focuses on problems to which neurologically impaired children are particularly susceptible, and excludes acute, easily diagnosed conditions that might be found on the initial evaluation, such as an ear infection or another illness causing pain or distress. As a start, consider all the diagnoses listed in Table 1 and obtain the laboratory tests in Table 2. Of course, one can alter the laboratory workup according to the clinical situation.
The more common diagnoses discussed here are grouped by organ system, followed by less common but equally important conditions listed in an arbitrary order based on experience rather than by any published studies, as none exist.
Constipation is extremely common in children with severe neurologic disorders, and the condition is a common cause of pain.2,3 However, it is easily overlooked by parents and providers alike. Many children experience overflow stool output, for example, despite a large stool burden. In this case, the child may produce daily stool that is not firm, and the problem may escape attention.
An abdominal radiograph is a useful screen. Many radiologists don’t report stool burden unless asked specifically to do so. The pediatrician can either ask this question when ordering the x-ray or become comfortable with making this diagnosis upon inspection of the film. If significant constipation exists, often an outpatient regimen will work,4 or, if this is not successful or practical, an inpatient clean-out with polyethylene glycol solutions may be required.
Also consider other gastrointestinal causes, such as esophagitis secondary to gastroesophageal reflux. Many neurologically impaired patients have gastric motility problems, accompanied by retching and gagging. An empiric trial of an antacid such as a proton pump inhibitor (PPI), if no other obvious cause for pain is found, can be helpful. If the patient does not improve, discontinue the medication. If a gastrostomy tube is in place, check a gastric pH after treatment to maximize therapy. Check the gastric pH between feedings when possible so the solution is not buffered by formula. Gastric pH strips are readily available and the pH can be checked at the bedside. Some patients require the addition of an H2 blocker to a PPI to achieve a goal pH of 4.5 or greater.
These patients also can suffer from gastritis, ulcers, or eosinophilic esophagitis, all of which can cause pain, but diagnosis in these cases requires endoscopy, which is more of a second-line diagnostic test when nothing else has been found.
Visceral hyperalgesia can cause pain, but the pain in this situation is associated with feeding and may present with retching or vomiting. Although erythromycin is a common medication used to improve motility in children, neurologically impaired children often respond to cyproheptadine,5 gabapentin, or the blenderized diet (regular food placed in a blender and fed through the gastrostomy tube).6 In a patient with a gastrostomy tube, ask the family to try venting the tube if bloating or excess gas is present.
Pancreatitis is not unusual in this population. The use of valproic acid in particular is associated with pancreatitis. Lipase and amylase levels are useful screens for this diagnosis.
Some experienced clinicians note that patients who are tube fed seem to have an increased incidence of gallstones,7 although clear evidence of an association is lacking. Of course, any patient on total parenteral nutrition (TPN) is at increased risk for this problem. Liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (APT), or bilirubin may be elevated, although these tests are not particularly sensitive or specific for cholelithiasis. Abdominal ultrasound is the procedure of choice to diagnose gallstones, and a useful test for children who exhibit excessive crying and irritability.8
Nonambulatory patients are osteopenic and susceptible to pathologic fractures. These may occur not just after obvious trauma, but also with physical therapy. Usually, a detailed and careful physical exam can detect the fracture. When in doubt, a skeletal survey may be required in the most difficult cases, but it is not routinely necessary. Parents are often the best at locating an area of tenderness or a movement that causes pain.
Dislocation of the hip
Children with spasticity are at risk for hip dislocation, and this can cause pain as well. Often the pain is more of a problem when hips are subluxed rather than completely dislocated. Subluxed hips move in and out of the acetabulum, and this especially causes pain. On physical examination, hip abduction is decreased. Anteroposterior (AP) pelvic radiographs are a useful screen for this problem. Many patients with hip dislocation do not have pain, so this finding alone does not necessarily mean that the dislocation is causing the problem. If it is a cause of pain, it tends to occur with activities that require abduction, such as diaper changes or movement of the hips. Some patients seem to have pain while in sitting in their wheelchair.
Nonambulatory patients also are at increased risk for kidney stones because of excessive calcium excretion. In addition, stones may be associated with topiramate use9 and the ketogenic diet.10 Hematuria should raise suspicion for this diagnosis. Stones often may be visible on abdominal radiographs, but not all are radiopaque. An ultrasound or abdominal computed tomography (CT) scan may be required to determine if stones are causing obstruction and possible pain.11 As with cholelithiasis, the finding of nephrolithiasis alone does not mean it is the cause of acute pain unless there is evidence of obstruction.
Urinary retention/bladder distention
Urinary retention is another problem common in children with severe neurologic impairment that can cause pain. Affected patients urinate infrequently but have large volumes with each urination. The bladder may be enlarged on palpation. Interestingly, many children have bladder distention, but this does not always cause as much pain as one would expect. If distention is causing discomfort, the child should improve after urinating or after catheterization.
Although spasticity alone is not believed to cause pain, uncontrolled muscle spasms, and especially rigidity, are painful and probably cause cramping. Adult patients with cerebral palsy who are able to communicate report frequent episodes of pain in the lower extremities, back, neck, shoulders, and buttocks.12 It follows that children who are unable to communicate have pain as well.
A markedly elevated creatine phosphokinase (CPK) level can provide a clue that muscle cramps are a significant problem.13 although no sensitivity or specificity data for this test as a screen are available in this population. Among children with the most severe neurologic impairment, those with pain presumed to be caused by spasticity or rigidity can have CPK levels in the thousands. This abnormality can cause confusion in diagnosis because muscle breakdown may also cause elevations in liver function tests such as AST and ALT, leading to a misguided workup for liver disease instead of the underlying muscle problem. These patients often respond to medications for spasticity such as baclofen, tizanidine, or diazepam. When the latter medication is used, it is best reserved for acute intermittent rather than daily use because of the development of tolerance. Referral to a physician familiar with treatment of spasticity may be required.
Paroxysmal sympathetic hyperactivity
When the child’s irritability is extreme and associated with marked vital sign changes, consider paroxysmal sympathetic hyperactivity (PSH), otherwise known as autonomic storming. This problem is seen in the most severely neurologically impaired children, such as those with hypoxic ischemic encephalopathy. The condition appears to be more common early after an injury and becomes less frequent with time for most children. These patients have tachycardia, hypertension, often fever, severe muscle spasm, sweating, and tachypnea, which can be easily confused with severe infection or sepsis. It is usually triggered by something that causes pain, so look for the same triggers in these cases as in the less severe situations discussed in this article.
Treatment of PSH has a limited evidence base. The usual first step in treatment is to select daily medications to control ongoing symptoms and minimize flare-ups. The second step is to choose as-needed (prn) medications for exacerbations.14 With regard to daily medications, baclofen, clonidine, beta blockers such as propranolol, and gabapentin are the mainstays of treatment. Experts vary on their choice of which medications to try first. When tachycardia and hypertension are severe, start with clonidine and/or propranolol. Some patients respond better to one or the other, but it is difficult to predict which one. Gabapentin has an excellent safety profile and is one of the first medications to use. Baclofen is helpful if marked rigidity or spasticity is apparent. Sometimes several or even all of these medications will be required. Bromocriptine also has been used. With regard to prn medications, narcotics such as morphine, and benzodiazepines such as diazepam, are the mainstays of treatment. Clonidine can be used on a prn basis as well, as long as hypotension does not occur. In the most extreme situations, admission to the intensive care unit and sedation with intravenous dexmedetomidine may be required.
Status dystonicus,15 or “dystonic storm,” has been described in patients with dystonic cerebral palsy and other underlying dystonic conditions. These patients experience severe muscle rigidity and agitation, with elevated CPK and other symptoms that overlap with PSH. The first step in the treatment of this condition is to use a benzodiazepine such as diazepam, which has superior muscle-relaxing properties compared with clonazepam or lorazepam. Consultation with neurology is needed if this condition is suspected.
Adverse reactions to administration/withdrawal of medications
Sometimes patients have an unusual or atypical reaction to a new medication. In this case, the irritability may have started around the time the new medication was initiated or increased. For example, levetiracetam can cause behavior change in some patients. Antihistamines can cause irritability rather than the expected sedation. Patients may develop serotonin syndrome from selective serotonin reuptake inhibitors (SSRIs), or neuroleptic malignant syndrome (NMS) from dopamine antagonists such as haloperidol, risperidone, olanzapine, ziprasidone, quetiapine, aripiprazole, and metoclopramide, as well as from abrupt withdrawal of levodopa. Neuroleptic malignant syndrome and serotonin syndrome have symptoms in common with PSH. Both can be associated with fever, tachycardia, muscle rigidity, hypertension, and agitation.
For patients undergoing continuous treatment for spasticity, withdrawal from medications is a notable cause of irritability. Baclofen, for example, cannot be stopped suddenly without signs of withdrawal including severe spasticity, sweating, itching, and extreme discomfort, and if the patient with a baclofen pump has severe irritability, pump malfunction is the most likely diagnosis until proven otherwise. Sudden discontinuation or missed doses of opioids or benzodiazepines cause similar symptoms.
Decubitus ulcers may cause discomfort. These are most common on bony prominences, such as the sacrococcygeal area, ischium, lateral elbows, occiput, and ear. Keep in mind that these ulcers may not cause as much pain as one would think and may not be the source of irritability, even when present.
Lagophthalmos is the inability to completely close the eyes with sleep. The condition can lead to corneal abrasions and pain. Look for signs of inflammation in the cornea and sclera. This can be treated with a lubricating ointment.
A dental abscess can cause severe pain, so a thorough oral exam is required. However, patients who are designated as nothing by mouth (NPO) and do not receive carbohydrates by mouth appear to be at reduced risk to develop caries.16
A major change in the home environment or routine can lead to irritability even in children with profound neurologic impairment. These changes may be overlooked in a routine medical history. Sometimes a long-term nurse has left, or a dramatic change has occurred in the life situation of a caretaker or parent.
Many neurologically impaired children have poor intestinal motility and undergo multiple courses of antibiotics, which puts them at risk for small intestine bacterial overgrowth. Symptoms include bloating from increased intestinal gas, flatulence, and abdominal pain. Diagnosis and treatment can be problematic, and consultation with gastroenterology may be required. One clue is excessive intestinal gas on abdominal x-ray or abdominal distention on exam.
Children with severe neurologic impairments may have dysfunction of the adrenal pituitary axis, and their inadequate stress response can contribute to irritability. Clues include a history of otherwise unexplained hypoglycemia, hypotension with relatively minor infections, or after surgery.
Seizures may be considered if obvious mental status changes or seizure-like movements are associated with irritability. An electroencephalogram obtained during an episode can exclude this diagnosis. However, seizures are an unusual cause of agitation or apparent pain as an isolated finding. Also, migraine headaches can cause irritability. In this case, the episodes are periodic and a strong family history of migraines usually exists.
Increased intracranial pressure may cause headaches and irritability. This is most common in children with a ventriculoperitoneal shunt, but of course also occurs with intracranial bleeding. If the patient has signs of increased intracranial pressure, such as depressed mental status, vomiting, or bradycardia with hypertension, consider a head CT scan, rapid sequence magnetic resonance imaging, and/or neurosurgical consultation.
Apparent increases in persistent pain have been reported in the weeks following surgical procedures such as osteotomies for hip dislocation and Nissen fundoplication.17
Finally, there are cases for which no cause for neuroirritability can be found. In these cases, one can treat empirically even if a thorough search does not yield a clear diagnosis. Of course, for any cause of neuroirritability, nonpharmacological interventions such as cuddling, repositioning, weighted blankets, and massage are great first steps.18
Some children experience relief from vibration. If so, vibrating snakes or tubes can be easily purchased online. With regard to medications, gabapentin is the first-line medication in idiopathic irritability because of its safety profile. It can be very effective. Start with a low dose and increase every 3 to 7 days to avoid excessive sedation, although this sedation effect can be put to good use at bedtime. Nortriptyline, amitriptyline, or serotonin-norepinephrine reuptake inhibitors (SNRIs) may be added to gabapentin.
Treating children with severe neurologic impairments for excessive crying and irritability can be frustrating, but also deeply rewarding when a thoughtful approach is combined with shared decision making with families. Diagnosis and management require patience and persistence, and sometimes educated trial and error. Once the approach is explained to families, most become partners in the search for the best treatment and appreciate a physician who is willing to stay with them until a solution can be found.
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