Typically, the primary care pediatrician is the first healthcare provider to encounter a child having a neurologic emergency, the most commonly encountered of which is status epilepticus. While status epilepticus is easily recognized, other less common neurologic emergencies can lead to significant morbidity and mortality if unrecognized. Many of these emergent conditions begin with common primary care complaints. Anticonvulsant hypersensitivity syndrome (AHS), for example, typically begins with fever and an exanthem. Allowed to progress to its full form, AHS carries a mortality rate of 10%.1 In this article, we review neurologic emergencies that may present to a primary care clinic as common pediatric complaints, such as exanthematous rash, fever, and muscle spasms.
MANAGING STATUS EPILEPTICUS IN THE PRIMARY CARE CLINIC
Because the incidence of seizures and epilepsy is highest in childhood, status epilepticus is common. As many as 10% of febrile seizures constitute status epilepticus due to prolonged duration, and 20% of epilepsy patients develop status within 5 years of diagnosis, often as their first seizure.1
The first rule of seizure management is calm observation and assessment of the patient. Seizure is a clinical diagnosis, and not all patients with jerking movements are seizing. Physicians should assess mental responsiveness and suppressibility of the movement, ensuring that airway, breathing, and circulation are addressed first and foremost. Cyanosis and inadequate air exchange are common during the tonic phase of a seizure and may require simple airway support such as a jaw thrust or oral airway. Supplemental oxygen is a simple, routine intervention. Ninety percent of all seizures stop without intervention within 2 minutes, and 95% within 5 minutes.2-4
The well-known definition of status epilepticus includes either 30 minutes of continuous seizure activity or recurrence of seizure prior to return to baseline mental status. To allow prompt seizure relief, administration of medications to interrupt seizure activity should begin long before the 30-minute mark. Some studies suggest that earlier intervention may lessen the likelihood of refractory status epilepticus.5
Guidance for medications used in the treatment of status epilepticus is provided in the Figure (see page 880).1,6 Doses are reviewed in Table 1 (see page 880). The doses and sequence of medications in this protocol maximize efficacy while minimizing adverse effects such as respiratory suppression and hypotension. After each dose of medication, adequate time should be allowed for the dose to take effect to avoid administering unnecessary additional doses. The physician also should look for treatable causes of status epilepticus that require different interventions, such as hypoglycemia and hyponatremia.
Benzodiazepines are first-line medications because of their rapid delivery and high efficacy, with lorazepam being the preferred parenteral agent.6 Rectal diazepam is a very useful addition to the medication armamentarium of a general outpatient clinic. Use of rectal diazepam allows prompt and effective treatment if IV access is delayed or difficult.7 A second dose of benzodiazepine can be administered if seizure activity persists or recurs, but repeated doses beyond this will result in progressive respiratory suppression and increased recovery time. If a second dose is required, transport arrangements to an inpatient or emergency facility should be underway.
Figure. Guidelines for management of status epilepticus in the pediatric office setting.
Should convulsive seizure activity persist after benzodiazepine administration, phenytoin or fosphenytoin should be used next, if available in the clinic. Advantages of fosphenytoin include more rapid infusion time, intramuscular administration capability, and lack of caustic effects if IV infiltration occurs. Although less likely, hypotension can complicate phenytoin or fosphenytoin infusions, so cardiac monitoring is required for both medications.
Phenobarbital completes the usual initial protocol for treatment of status epilepticus. Its use is delayed due to the common occurrence of respiratory depression and hypotension, particularly if the patient has already received other acute treatments such as a benzodiazepine. Most outpatient clinics would not support the possible complications of phenobarbital infusions. Phenobarbital has been used in infants prior to administering phenytoin, mostly because the latter medication is difficult to maintain at therapeutic levels during ongoing maintenance therapy. Phenytoin may be as effective in terminating status epilepticus in this age group, but comparison studies have not been performed.
Dosing and Infusion Guidelines for Treatment of Status Epilepticus
Once overt seizure activity has ceased, the patient's respiratory status should be monitored closely as lingering medication effects combine with postictal suppression to inhibit respiratory drive. Many patients have shallow, ineffective respirations but respond well to stimulation or assisted ventilation with a bag-mask. If a patient remains deeply unresponsive or is awake and has not returned to baseline mental status, the possibility of continued nonconvulsive status epilepticus should be considered (the diagnosis of which requires an urgent electroencephalogram). Finally, a diagnostic workup should be pursued if the cause of the seizure is not obvious. Major considerations requiring prompt intervention include meningitis, sepsis, and trauma.
Although fever and rash are encountered frequently in the office, the pediatrician should have a high index of suspicion for AHS in children who are taking antiepileptic drugs (Sidebar 1). While the true incidence of AHS is unknown, it is estimated to be between 1 in 1,000 and 1 in 10,000 exposures.8 AHS is an acute, potentially life-threatening, idiosyncratic drug reaction that has also been referred to as DRESS syndrome, an acronym for "Drug Rash with Eosinophilia and Systemic Symptoms."9 Currently there is no consensus for a single term for this syndrome.
Studies have suggested an autoimmune mechanism involving the accumulation of toxic metabolites.8,10 Phenytoin, phenobarbital, and carbamazepine share a similar aromatic ring structure. There is some disagreement in the literature regarding the presence of an aromatic ring in lamotrigine and its propensity for cross-reaction with phenytoin, phenobarbital, and carbamazepine.8-10 However, there is no doubt that lamotrigine has caused AHS.11,12 Therefore, for the purposes of this discussion, we will group lamotrigine with the common aromatic antiepileptic drugs. The aromatic compounds in these medications are metabolized by the cytochrome P450 system into arene oxide, which may trigger the autoimmune response seen in AHS.10,13
The typical child with AHS presents with a triad of fever, rash, and lymphadenopathy. Laboratory findings that may assist in the diagnosis of AHS include lymphocytosis, thrombocytopenia, and eosinophilia. Multi-organ involvement may evolve 1 to 2 weeks after the rash erupts and can involve the liver, kidney, central nervous system, and lungs. The rash typically begins as diffuse erythema and skin tenderness with potential progression to severe cutaneous and mucosal exfoliation. The severity and extent of the mucocutaneous and systemic manifestations allow classification along a spectrum of disorders including erythema multiforme, Stevens Johnson syndrome, or toxic epidermal necrolysis. The mortality rate of toxic epidermal necrolysis is approximately 40%.8
In addition to the skin manifestations and lymphadenopathy, internal organ involvement can occur in AHS, usually evolving over 1 to 2 weeks after the rash erupts. Hepatotoxicity has been reported in up to 64% of patients.10 Transaminase elevations can be greater than 25 times the upper limit of normal at presentation. Most important, mortality in AHS has been directly correlated with the degree of hepatic involvement. Fulminant hepatitis, pancreatitis, nephritis, myositis, or encephalopathy can occur in severe cases. Hypothyroidism can develop as a late sequela.
AHS usually starts within the first 2 to 8 weeks of antiepileptic drug therapy. Nearly every anticonvulsant has been implicated with the development of AHS. As already mentioned, the risk is thought to be greatest in medications whose chemical structure contain an aromatic ring (eg, phenytoin, carbamazepine, and phenobarbital). The cross-reactivity among these drugs has been reported to be as high as 70% to 80%, while the cross-reactivity of these drugs with lamotrigine is controversial. Recently, the Food and Drug Administration revised the safety labeling of oxcarbazepine due to reports of AHS. One case-control study comparing the incidence of AHS from phenobarbital, carbamazepine, phenytoin, and lamotrigine showed that the relative risk in the first 8 weeks of treatment was highest for carbamazepine, while after 8 weeks, the risk was highest for lamotrigine.14
The rate of AHS from lamotrigine can be lessened exponentially by slow dose escalation following the manufacturer's instructions. Patient-specific factors also may influence the risk of developing AHS. Cancer and HIV patients develop AHS at a higher rate, and first-degree relatives of people with AHS have a fourfold risk compared with the general population.15
The most essential treatment for AHS consists of immediate withdrawal of the anticonvulsant drug. This usually results in complete recovery; however, acute management depends on the severity of the mucocutaneous and systemic manifestations. Supportive care with fluid replacement and pain relief is essential. If the patient requires continued anti-convulsant therapy, consideration must be given to the potential cross-reactivity of the replacement drug, provoking continuation or relapse of AHS. Although cases of cross-reactivity with oxcarbazepine have not been reported, theoretical concern exists because of chemical structure similarities with carbamazepine. Topiramate and zonisamide each contain a sulfa moiety and so, theoretically, share a common basis for causing AHS and would not be wise substitutes for each other. Valproate should be avoided if hepatitis is present. Benzodiazepines provide effective short-term anticonvulsive effects and lack cross-reactivity risks.
There is considerable controversy regarding the efficacy of corticosteroids in these patients. Systemic corticosteroids have been widely used in patients with severe AHS (such as Stevens Johnson syndrome or toxic epidermal necrolysis). For example, a 1997 prospective study of 16 children suggested that methylprednisolone reduces the period of fever and acute skin eruptions.16 However, other studies have demonstrated significantly greater rates of infection and medical complications in corticosteroid-treated patients.8 Due to the ongoing controversy regarding the potential risk of immunosuppression and infection, there is currently no formal recommendation for using corticosteroids for the treatment of Stevens Johnson syndrome or toxic epidermal necrolysis.
NEUROLEPTIC MALIGNANT SYNDROME
Medications that block dopamine receptors are used commonly in a wide array of childhood disorders, such as chronic nausea or emesis, gastroesophageal reflux, autism, tic disorders, and bipolar disorder. However, these medications can cause neuroleptic malignant syndrome, a syndrome of hyperthermia, autonomic dysfunction, altered mental status, and muscular rigidity. This diagnosis should be considered in any patient taking dopamine-antagonists who presents with fever.
The annual incidence of neuroleptic malignant syndrome in the United States is 0.5% to 2.4% of patients exposed to neuroleptic, also known as antipsychotic, agents or other dopamine antagonists. The reported mortality from neuroleptic malignant syndrome ranges from 4% to 20%. 17 The syndrome can occur at any time during treatment with dopamine antagonists but is most common during the first 3 to 9 days after initiation of therapy.
The diagnosis of neuroleptic malignant syndrome is made clinically, while simultaneously ruling out other suspected conditions. The differential diagnosis includes malignant hyperthermia, central anticholinergic syndrome, serotonin syndrome, sepsis, encephalitis, status epilepticus, delirium tremens, ingestion of stimulants or hallucinogens, and heatstroke. Malignant hyperthermia resembles neuroleptic malignant syndrome but typically occurs during exposure to inhalational anesthestic agents and depolarizing muscle relaxants. Central anticholinergic syndrome may include fever and mental status changes also seen in neuroleptic malignant syndrome, but the degree of fever is less. The classic symptoms of central anticholinergic syndrome include decreased sweating, mydriasis, dry mouth, and urinary retention. These are in contrast to the diaphoresis, rigidity, and rhabdomyolysis seen in neuroleptic malignant syndrome. Serotonin syndrome shares many similarities with neuroleptic malignant syndrome. These syndromes usually can be distinguished by a history of selective serotonin reuptake inhibitor use and the presence of gastrointestinal problems such as diarrhea.
Medications Associated With Neuroleptic Malignant Syndrome and Acute Dystonic Reaction
Laboratory testing can supply supportive data, but there is no confirmatory test for neuroleptic malignant syndrome. According to the Diagnostic and Statistical Manual for Mental Disorders, fourth edition (DSM-IV),18 diagnosis requires increased temperature and muscle rigidity accompanied by two or more of the following: diaphoresis, tremor, dysphagia, altered mental status, tachycardia, incontinence, dysregulation of blood pressure, leukocytosis, and elevated creatine Phosphokinase.17 Although the pathophysiology of neuroleptic malignant syndrome is poorly understood, the common precipitant is reduced dopamine in the central nervous system.19 Dopamine antagonists associated with neuroleptic malignant syndrome include primarily neuroleptic antipsychotics, but also related drugs such as anti-emetics, motility agents, sedatives, and, less often, atypical antipsychotics (Table 2).
As with AHS, the most important therapy for children with neuroleptic malignant syndrome is identification and elimination of the offending medication. Treatment is primarily supportive and includes fluid replacement, blood pressure support, and temperature reduction. Respiratory failure may occur secondary to chest wall rigidity. Renal failure may also occur, necessitating urgent hemodialysis. Bromocriptine, a centrally acting dopamine agonist, counters the effects of the offending dopamine antagonist Dantrolene also commonly is used in the intensive care setting to induce skeletal muscle relaxation and decrease body temperature.
Like neuroleptic malignant syndrome, serotonin syndrome can present with hyperthermia in patients taking serotonergic medications (antidepressants and newer antipsychotics) for psychiatric conditions or migraines. Serotonin syndrome is a potentially life-threatening adverse drug reaction that results from intentional overdose, accidental overdose, or additive serotonergic properties between drugs. The widely publicized death in 1984 of an 18-year-old patient, Libby Zion, from the combination of meperidine and phenelzine demonstrates the potential additive effects of multiple serotonergic medications.20
Serotonergic medications are primarily used as antidepressants and migraine treatments, but newer antipsychotics can also increase serotonin. Numerous agents have been implicated in such reactions with serotonergic medications, including SSRI, antipsychotics, cold remedies, and alternative therapies (eg, St. John's wort; Sidebar 2) The addition of MDMA or "ecstasy" to SSRI therapy also has provoked serotonin syndrome.
Serotonin syndrome presents with neuromuscular changes, confusional states, and autonomic hyperarousal. Symptoms typically progress rapidly over minutes to hours. The majority of patients present within 24 hours of a medication initiation, overdose, or change in dosage.21 Confusion can be mild or present with frank hypomania and agitation. The neuromuscular changes range from tremor in the mildest cases to clonus, hyperreflexia, and rigidity. The autonomic manifestations are varied and also present along a spectrum from mild to severe. A patient with moderate symptoms may demonstrate tachycardia, hypertension, diaphoresis, and hyperthermia. The gastrointestinal response to heightened autonomic activity results in hyperactive bowel sounds, vomiting, and diarrhea.22 The combined effect of autonomic hyperexcitability and rigidity may produce core temperatures in excess of 41 degrees C.
Successful management of serotonin syndrome consists of identification and discontinuation of the offending drugs as well as supportive care. Medical management of autonomic instability, hyperthermia, and agitation may be required. Benzodiazepines are the mainstay for treatment of agitation and acute anxiety. Cyproheptadine, chlorpromazine, and methysergide (medications with 5-HT receptor antagonist properties) have demonstrated efficacy in moderate to severe cases. In particular, cyproheptadine, a first-generation antihistamine, generally is considered the recommended therapy for moderate to severe serotonin syndrome.
The incidence of serotonin syndrome is difficult to estimate, as suggested by a survey of primary care physicians in which 85% of respondents were unaware of the syndrome.23 Approximately 14% to 16% of patients who have an overdose of an SSRI (intentional or accidental) will have serotonin syndrome.22 However, given the sharp rise in prescriptions for SSRIs and other antidepressants, the incidence is thought to be increasing. The reported mortality rate ranges from 2% to 12%.21
Mild serotonin syndrome generally is a self-limiting disorder. However, due to the associated risks in severe cases, early recognition and appropriate aggressive management are essential.
DRUG-INDUCED MOVEMENT DISORDERS
In addition to neuroleptic malignant syndrome, neuroleptic medications also can cause many acute drug-induced movement disorders, such as dystonia, akathisia, tremor, tardive dyskinesia, and myoclonus. Among these, acute dystonic reactions are seen most commonly.24
Dystonia is a disorder of the central nervous system that results in involuntary, sustained, simultaneous contraction of agonist and antagonist muscles. The contraction of muscles results in twisting, repetitive movements, and painful, abnormal postures. Acute dystonic reactions reportedly occur in approximately 3% of patients exposed to dopamine-blocking medications. Haloperidol and other typical antipsychotics result in acute dystonic reactions in as many as 30% to 40% of patients.24,25 The atypical antipsychotics generally have a lower incidence of reactions. Anti-emetics and sedatives also cause this reaction (Table 2). Ninety percent of affected children develop the dystonia within the first 5 days of treatment, sometimes after a single dose.
Common dystonic movements include torticollis (horizontal turning of the head), tongue protrusion, facial grimacing, and opisthotonus. A particularly alarming dystonia is sustained upward eye deviation referred to as an oculogyric crisis. Intermittent or brief dystonic reactions may be mistaken for seizures. The history of exposure to dopamine antagonists, and the preservation of interactiveness will distinguish these two diagnoses. Dystonic reactions can be treated in the clinic with intravenous or intramuscular diphenhydramine or a benzodiazepine such as diazepam or lorazepam. Anticholinergic drugs such as benztropine or procychdine are also effective. Children may require several days of continued treatment with these rescue medications.
INTRATHECAL BACLOFEN WITHDRAWAL
Baclofen is an agonist of gamma-amino butyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. This medication has been widely used as an oral preparation to treat children with spasticity. Increasingly, surgically-implanted pumps provide more efficient medication delivery directly to the intrathecal space. Intrathecal baclofen (ITB) can reduce spasticity at a fraction of the oral dose and without the systemic side effects. However, the implanted infusion pump and the intrathecal catheter can malfunction, which can be life-threatening.26,27 As the use of ITB becomes more widespread among children with spasticity, particularly in the cerebral palsy population, it is imperative that primary care pediatricians are able to recognize and respond to this potentially deadly withdrawal syndrome.
Abrupt withdrawal of ITB can result from pump malfunction, catheter blockage or disconnection, or surgical removal secondary to infection of the pouch containing the pump. GG? withdrawal should be suspected if a child has a rapid return to baseline spasticity and rigidity. Withdrawal symptoms have been reported to occur between 12 and 72 hours after the discontinuation of baclofen.26 The symptoms may be difficult to differentiate clinically from those of neuroleptic malignant syndrome. Children may develop generalized seizures, mental status changes such as confusion or hallucinations, fever, muscle rigidity, hypotension, rhabdomyolysis, disseminated intravascular coagulation, multi-organ failure, and death. A recent review of reported cases of ITB withdrawal found that the majority of patients progressed to severe withdrawal over 1 to 3 days. However, prompt recognition and treatment was shown to interrupt this progression.
Management of ITB withdrawal involves replacement of the medication as soon as possible. In the interim, supportive measures and IV benzodiazepine, which also act as GABA-agonists, may be life-saving. Oral baclofen should be delivered at doses of 10 mg to 40 mg every 4 to 8 hours. Because of the systemic distribution of oral baclofen, oral replacement doses exceed the usual ITB dose by 50 to 100 times (ITB dose ranges from 100 to 400 meg/day).26 Oral baclofen alone usually will not suffice and must be combined with benzodiazepines in most cases.
Anticonvulsants, neuroleptics, and antispasticity agents are used with increasing frequency in the pediatric population. Each of the drugs discussed in this article has serious but potentially reversible adverse effects. Pediatric primary care providers must be aware of the potential emergencies associated with the use of these neurologic medications to provide prompt and effective treatment.
1. Phillips S, Shanahan R. Etiology and mortality of status epilepticus in children. A recent update. Arch Neurol. 1989;46(1):74-76.
2. Lowenstein D, Bleck T, Macdonald R. It's time to revise the definition of status epilepticus. Epilepsia. 1999;40(1): 120-122.
3. Mitchell W. Status epilepticus and acute serial seizures in children. J Child Neurol. 2002; 17(Suppl 1):S3643.
4. Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new-onset seizures in children last? Ann Neurol. 2001;49(5):659-664.
5. Alldredge BK, Wall DB, Ferriera DM. Effect of prehospital treatment on the outcome of status epilepticus in children. Pediatr Neurol. 1995;12(3):213-216.
6. Treiman D, Meyers P, Walton N, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;339(12):792-798.
7. Dreifuss F, Rosman N, Cloyd J, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med. 1998;338(26):1869-1875.
8. Lee W, Leung J, Chung B, et al. Spectrum of anticonvulsant hypersensitivity syndrome: controversy of treatment. J Child Neurol. 2004;19(8):6 19-623.
9. Kaur S, Sarkar R, Thami G, et al. Anticonvulsant hypersensitivity syndrome. Pediatr Dermatol. 2002;19(2):142-145.
10. Bessmertny O, Pham T. Antiepileptic hypersensitivity syndrome: clinicians beware and be aware. Curr Allergy Asthma Rep. 2002;2(1):34-39.
11. Schlienger R, Knowles S, Shear N. Lamotrigine-associated anticonvulsant hypersensitivity syndrome. Neurology. 1998;51(4):1172-1175.
12. Brown T, Appel J, Kasteler J, et al. Hypersensitivity reaction in a child due to lamotrigine. Pediatr Dermatol. 1999;16(1):46-49.
13. Sullivan J, Shear N. The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol. 2001;137(3):357-364.
14. Rzany B, Correia O, Kelly J, et al. Risk of Stevens Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study on severe cutaneous adverse reactions. Lancet. 1999;353(9171):2190-2194.
15. Kaminsky A, Moreno M, Diaz M, et al. Anticonvulsant hypersensitivity syndrome. Int J Dermatol. 2005;44(7):594-598.
16. Kakourou T, Klontza D, Soteropoulou F, et al. Corticosteroid treatment of erythema multiform major (Stevens Johnson Syndrome) in children. Eur J Paediatr. 1997;156(2):90-93.
17. Bhanushali M, Tuite P. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin. 2004;22(2):389-411.
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing; 1994.
19. Sachdev P. Neuroleptic-induced movement disorders: an overview. Psychiatr Clin N Am. 2005;28(1):255-274.
20. Asch D, Parker R. The Libby Zion case. One step forward or two steps backward? N Engl J Med. 1988;31 8(12):77 1-775.
21. Mason P, Morris V, Balcezak T. Serotonin syndrome: presentation of 2 cases and review of the literature. Medicine (Baltimore). 2000;79(4):201-209.
22. Boyer E, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
23. Mackay F, Dunn N, Mann R. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49(448):871-874.
24. Diederich N, Goetz C. Drug-induced movement disorders. Neurol Clin. 1998;16(1):125-139.
25. McMahon W, Filloux F, Ashworth J, et al. Movement disorders in children and adolescents. Neurol Clin. 2002;20(4):1101-1124.
26. Coffey R, Edgar T, Francisco G, et al. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially lifethreatening syndrome. Arch Phys Med Rehabil. 2002;83(6):735-741.
27. Zuckerbraun N, Ferson S, Albright A, et al. Intrathecal baclofen withdrawal: emergent recognition and management. Pediatr Emerg Care. 2004;20(11):759-764.
Dosing and Infusion Guidelines for Treatment of Status Epilepticus
Medications Associated With Neuroleptic Malignant Syndrome and Acute Dystonic Reaction