CLINICAL SYMPTOMS

Clinical features of NCSE include cognitive changes, speech abnormalities, affective disturbances, psychosis, poor impulse control, and bizarre behaviors (Table 3). Some patients develop ictal phenomena resembling catatonia or clinical and EEG changes that mimic neuroleptic malignant syndrome (NMS).20-23


Table 3
Clinical features that raise suspicion of NCSE

Catatonia. Lim et al24 described three patients with EEG-confirmed NCSE that manifested as ictal catatonia. A prolonged, trance-like, stuporous state during epilepsy has been reported, as has CPSE presenting with psychogenic unresponsiveness. Drury et al25 described a patient who presented with catatonia and increased muscle tone but had prominent EEG abnormalities implicating an organic cause.

Among 29 patients with acute catatonic syndromes, epileptic activity was identified in 4. One patient with absence status was diagnosed with NMS during the catatonic period.26 Conversely, the commonality of clinical features has led to misdiagnosis of psychogenic catatonia as NCSE. EEG is necessary to exclude NCSE in these cases.

NMS. Yoshino et al27 described two patients taking neuroleptics who met criteria for NMS and had EEG changes consistent with NCSE. They later reported another patient with NCSE complicating NMS; the point at which NCSE developed was unknown, however, because EEG activity was not recorded at NMS onset.28 Based on NMS diagnostic criteria proposed by Caroff et al,29 these patients could have developed NCSE mimicking NMS.

EEG FOR DIAGNOSIS

Candidates. Because differentiating NCSE from similar conditions can be difficult, use EEG to confirm your clinical observations. No guidelines exist, but consider EEG when the patient’s history suggests NCSE. Ask the patient or family about:
• changes in mental status from baseline, especially new-onset catatonia or unexplained altered consciousness
• duration of events
• presence or absence of motor activity
• behavioral fluctuations
• presence or absence of automatisms or blinking.

List the patient’s medications, ask about illicit substance or alcohol use, and gather a comprehensive history of medical, neurologic, and psychiatric illnesses. Include NCSE in the differential diagnosis of elderly patients with acute prolonged confusion. Try to obtain EEG early to differentiate focal from secondary generalized seizures.

EEG patterns.Table 4 summarizes NCSE diagnostic criteria. NCSE shows characteristic patterns in ASE and CPSE,9,10,16,23 and EEG changes can be continuous or nearly continuous in both.

In ASE, a generalized, bilaterally synchronous, rhythmic, 3- to 3.5-second spike with a bifrontal maximum is seen in 40% of cases.30 Also described in ASE are fragmented spike waves, multiple spikes and waves, and generalized bilateral discharges with focal predominance. This last pattern might suggest an underlying focal origin of the epileptic discharge with secondary generalization.31,32

In CPSE, less-synchronous epileptiform activity has been described, including rhythmical slow, rhythmic spikes, or rhythmic spike and slow waves. Two types of CPSE of frontal origin have been described:

• Type 1 presents clinically with mood disturbance and minimal confusion. EEG shows a frontal focus with a normal background.
• Type 2 presents clinically with confusion. EEG shows bilateral asymmetric frontal discharges.8

Not always clear. Making a clear distinction between primary and secondary generalization on EEG is not always possible.15 In a large series of NCSE cases,31 ictal discharges on EEG were:

• generalized in 69%
• diffuse with focal predominance in 18%
• focal in 13%.

Although most EEGs showed a generalized pattern, many cases probably started focally with immediate generalization. Morphologies seen—in descending order of frequency—were atypical spike and wave, multiple spike waves, rhythmic delta with intermittent spikes, and typical spike and wave patterns. Ictal discharge frequency also was variable and <3 Hz in 79% of cases.
Distinguish between ictal and interictal EEG findings with epileptiform activity, because only the former is diagnostic for NCSE. Intravenous benzodiazepines might be necessary during EEG to verify the diagnosis.33

NCSE has developed after electroconvulsive therapy (ECT), but a cause-effect relationship is debatable. Interictal and abnormal EEG findings after ECT may be misdiagnosed as NCSE.34

Neuroimaging has limited clinical value because of the need for patient cooperation and specialized equipment.4 Head CT or MRI can exclude structural abnormalities. PET and SPECT show increased metabolism and blood flow, respectively, in NCSE. MR spectroscopy shows elevated lactate and decreased N-acetyl aspartate.


Table 4
EEG findings that support a clinical diagnosis of NCSE

HALTING ICTAL ACTIVITY
To rapidly stop ictal activity—the main goal of treatment—recognizing and correcting precipitant factors is vital:

• Consider discontinuing medications that could lower the seizure threshold.
• Order a complete blood count, serum electrolytes, calcium, arterial-blood gas, liver and renal function tests, urine toxicology screen, and serum antiepileptic drug concentrations.
• When possible, obtain neuroimaging and EEG in the emergency room for accurate diagnosis and prompt treatment.12

Medications. Benzodiazepines such as lorazepam, diazepam, and clonazepam are used most often to interrupt seizure activity. Use them cautiously in medically fragile patients, however, to prevent hypotension and respiratory depression.

Response to benzodiazepines might be transient, lasting only hours or days. For instance, diazepam’s anticonvulsant effect may last <20 minutes and lorazepam’s ≤12 hours. Longer-term agents include phenytoin, valproic acid, carbamazepine, and phenobarbital.

Newer antiepileptics—such as lamotrigine, levetiracetam, or topiramate—have been used with varying results, and their role in first-line treatment of NCSE is evolving. Rarely, the antiepileptic tiagabine precipitates or worsens NCSE.4,13,14

Related resources
• Epilepsy Foundation. www.epilepsyfoundation.org
• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals, (888) 667-8367. www.nmsis.org

Drug brand names
Carbamazepine • Tegretol, Carbatrol
Clonazepam • Klonopin
Diazepam • Valium
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lithium carbonate • Lithobid, Eskalith CR
Lorazepam • Ativan
Phenobarbital • Luminal
Phenytoin • Dilantin
Tiagabine • Gabitril
Topiramate • Topamax
Valproic acid • Depakote

Disclosure
The authors report no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Acknowledgment
Dr. Goveas was a geriatric psychiatry fellow, University of Pennsylvania, when he wrote this article in collaboration with his mentors, Drs. Caroff and Riggio.

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