Silvana Riggio, MD

Nonconvulsive status epilepticus (NCSE) is marked by neurobehavioral disturbances that resemble primary psychiatric disorders. Mistaken diagnosis and delayed treatment increase the risk of neurologic damage, so recognizing NCSE symptoms early is important.

To help you make a timely diagnosis, this article describes:

• neuropsychiatric manifestations of NCSE
  
• how to narrow the differential diagnosis by reviewing clinical symptoms and using electroencephalography (EEG)
  
• techniques used to rapidly halt ictal activity.
  

Box

Triggers, neurologic symptoms

NCSE is an acute but treatable medical emergency that calls for assessing and supporting cardiac and respiratory function, monitoring vital signs, temperature reduction, and fluid replacement. Prognosis is usually good unless NCSE is associated with a serious medical illness (Box).^1-11

Many metabolic, neurologic, pharmacologic, and medical abnormalities can precipitate NCSE (Table 1). The most common causes are hypoxia/anoxia, stroke, infection, subtherapeutic antiepileptic levels, alcohol and benzodiazepine intoxication/withdrawal, and metabolic abnormalities.^4,7,10,12

NCSE manifests as absence status epilepticus (ASE) or complex partial status epilepticus (CPSE). A generally accepted diagnostic definition is ≥30 minutes of behavioral change from baseline, with diagnostic EEG findings.^4,13 EEG is indispensable because the clinical manifestations of NCSE are predominantly behavioral, with minimal or no motor activity.

Table 1

Clinical factors that may precipitate NCSE

Medical	Recent infection, hyperventilation, trauma, menstruation, pregnancy, renal dialysis, postoperative period, sleep deprivation
Metabolic	Hypoparathyroidism, renal failure, hyper/hyponatremia, hyper/hypoglycemia, hypocalcemia
Neurologic	Mental retardation, dementia, stroke
Pharmacologic	Low serum levels or abrupt discontinuation of anticonvulsants, alcohol intoxication/withdrawal, benzodiazepine withdrawal lithium and neuroleptic use, psychotropic overdose
Source : References 9,10,12,16

ASE, a primary generalized process, is characterized by confusion or diminished responsiveness; it may be associated with occasional blinking or other minor motor activity and can last for hours to days. It usually occurs in patients with known epilepsy, particularly absence seizures.

ASE is reported primarily in children, although de novo cases have been described in elderly patients with no history of epilepsy.^10,14

CPSE is usually associated with a history of focal epilepsy and vascular disease. CPSE has a focal onset, with subsequent secondary generalization. Onset is usually temporal in origin but also can be extratemporal.

Patients with CPSE often cycle between an “epileptic twilight state” with confusion and complete unresponsiveness with stereotyped automatisms. It can present with marked behavioral fluctuation or a change in mental status and is generally followed by a prolonged postictal state.^4,7,13-15 Several NCSE cases have occurred in patients with no history of seizures.^9,10,16

Historically, CPSE was reported to be less common than ASE, but this misconception was most likely caused by failure to recognize CPSE’s clinical presentation and rapid generalization on EEG.^7,15

Neuropsychiatric features

Patients with NCSE may be referred for evaluation of an array of behavioral changes commonly seen in psychiatric practice. The differential diagnosis is extensive (Table 2) and includes neurologic and medical conditions often associated with catatonic syndrome.^17,18

In a retrospective study, Kaplan¹² assessed clinical presentations and reasons for diagnostic delay in 23 adults eventually diagnosed with NCSE. Presenting symptoms included:

• confusion, agitation, aggressive behavior
  
• lethargy, mutism, verbal perseveration, echolalia
  
• delirium, blinking, staring, chewing or picking behaviors
  
• tremulousness or myoclonus
  
• bizarre behavior (inappropriate laughing, crying, or singing)
  
• rigidity with waxy flexibility
  
• delusions, hallucinations.
  

Clinicians mistook hallucinations and mood lability for a primary psychiatric condition in 7 patients, presumed catalepsy was psychogenic in 3 patients, and thought obtundation was caused by alcohol or drug intoxication in 4 cases.

A prospective study of 22 patients with NCSE found that 7 had a history of psychotic depression, schizophrenia, self-mutilation, bipolar disorder, or episodic severe aggression; 12 of 18 with ASE had a history of epilepsy, and 3 of 4 with CPSE had experienced seizures associated with cerebrovascular accident, right cerebral embolus, and thiazide-induced hyponatremia, respectively.¹⁶

 

Table 2

Differential diagnosis of NCSE

Metabolic disorders	Hypo/hyperglycemia, hypercalcemia, Addison’s disease, Cushing’s disease, uremia
Neurologic disorders	Stroke, CNS tumors, closed head trauma, transient global amnesia, seizures, inflammatory and infectious encephalopathies
Psychiatric disorders	Schizophrenia, mood disorders, catatonia, malignant catatonia, somatoform disorders, conversion disorder, Asperger’s syndrome, malingering
Toxic disorders	Toxic encephalopathy, neuroleptic malignant syndrome, serotonin syndrome, alcohol and sedative-hypnotic withdrawal, drugs (lithium toxicity, tricyclics, baclofen, tiagabine, overdose)
Source: Reference 17,18

NCSE in the elderly can be difficult to diagnose, especially in patients with comorbid severe medical illnesses and other confusional states.⁴CPSE with possible generalization is more common than ASE in the elderly. Hyperreligiosity, intermittent agitation, motor perseveration, ictal fear, catatonic signs, delusional preoccupation, and auditory and visual hallucinations have been observed during NCSE in the elderly and misdiagnosed as primary psychiatric conditions.

Cerebrovascular disease, tumors, and trauma are the most common causes of late-life NCSE.^4,19 De novo NCSE occasionally presents:

• after benzodiazepine withdrawal
  
• with neuroleptic, tricyclic antidepressant, or lithium treatment^10,16
  
• with metabolic abnormalities and nonpsychotropic medications.¹⁰
  

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

Domain	Features
Cognitive changes	Prolonged confusion, executive dysfunction, obtundation, attention/memory difficulties, lack of initiative, perseveration, stupor
Speech	Poverty of speech with monosyllabic answers, verbal perseveration, echolalia, palilalia, aphasia, paraphasic errors, confabulation, mutism
Affective	Prolonged fear, affective indifferent state with blank facial expression, hypomania, psychotic depression, inappropriate laughing and crying, anxiety states
Psychosis	Visual, auditory and cenesthetic hallucinations, delusions
Impulse control	Hostility, agitation, violence, groping, genital manipulation, picking, posturing
Others	Catatonic signs, autonomic disturbances
Source: References 5,7-9,12,15-17,20-23

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 summarized 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.

Table 4

EEG findings that support a clinical diagnosis of NCSE

Clear-cut criteria
Frequent or continuous focal seizures, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution
Frequent or continuous generalized spike wave discharges:
in patients without history of epilepsy in patients with epilepsy, when discharges show significant changes in intensity or frequency compared with baseline EEG
Periodic lateralized epileptiform discharges (“PLEDs”) or bilateral periodic epileptiform discharges (“biPEDs") occurring in patients with coma from generalized tonic-clonic status epilepticus (subtle SE)
Probable (equivocal) criteria
Patients with acute cerebral damage who also show frequent or continuous EEG abnormalities without previous similar findings
Patients with epilepsy who show frequent or continuous generalized EEG abnormalities and similar interictal EEG patterns but whose clinical symptoms suggest NCSE
Source: References 4,12-14,17

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

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.

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

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.

Nonconvulsive status epilepticus (NCSE) is marked by neurobehavioral disturbances that resemble primary psychiatric disorders. Mistaken diagnosis and delayed treatment increase the risk of neurologic damage, so recognizing NCSE symptoms early is important.

To help you make a timely diagnosis, this article describes:

• neuropsychiatric manifestations of NCSE
  
• how to narrow the differential diagnosis by reviewing clinical symptoms and using electroencephalography (EEG)
  
• techniques used to rapidly halt ictal activity.
  

Box

Triggers, neurologic symptoms

NCSE is an acute but treatable medical emergency that calls for assessing and supporting cardiac and respiratory function, monitoring vital signs, temperature reduction, and fluid replacement. Prognosis is usually good unless NCSE is associated with a serious medical illness (Box).^1-11

Many metabolic, neurologic, pharmacologic, and medical abnormalities can precipitate NCSE (Table 1). The most common causes are hypoxia/anoxia, stroke, infection, subtherapeutic antiepileptic levels, alcohol and benzodiazepine intoxication/withdrawal, and metabolic abnormalities.^4,7,10,12

NCSE manifests as absence status epilepticus (ASE) or complex partial status epilepticus (CPSE). A generally accepted diagnostic definition is ≥30 minutes of behavioral change from baseline, with diagnostic EEG findings.^4,13 EEG is indispensable because the clinical manifestations of NCSE are predominantly behavioral, with minimal or no motor activity.

Table 1

Clinical factors that may precipitate NCSE

Medical	Recent infection, hyperventilation, trauma, menstruation, pregnancy, renal dialysis, postoperative period, sleep deprivation
Metabolic	Hypoparathyroidism, renal failure, hyper/hyponatremia, hyper/hypoglycemia, hypocalcemia
Neurologic	Mental retardation, dementia, stroke
Pharmacologic	Low serum levels or abrupt discontinuation of anticonvulsants, alcohol intoxication/withdrawal, benzodiazepine withdrawal lithium and neuroleptic use, psychotropic overdose
Source : References 9,10,12,16

ASE, a primary generalized process, is characterized by confusion or diminished responsiveness; it may be associated with occasional blinking or other minor motor activity and can last for hours to days. It usually occurs in patients with known epilepsy, particularly absence seizures.

ASE is reported primarily in children, although de novo cases have been described in elderly patients with no history of epilepsy.^10,14

CPSE is usually associated with a history of focal epilepsy and vascular disease. CPSE has a focal onset, with subsequent secondary generalization. Onset is usually temporal in origin but also can be extratemporal.

Patients with CPSE often cycle between an “epileptic twilight state” with confusion and complete unresponsiveness with stereotyped automatisms. It can present with marked behavioral fluctuation or a change in mental status and is generally followed by a prolonged postictal state.^4,7,13-15 Several NCSE cases have occurred in patients with no history of seizures.^9,10,16

Historically, CPSE was reported to be less common than ASE, but this misconception was most likely caused by failure to recognize CPSE’s clinical presentation and rapid generalization on EEG.^7,15

Neuropsychiatric features

Patients with NCSE may be referred for evaluation of an array of behavioral changes commonly seen in psychiatric practice. The differential diagnosis is extensive (Table 2) and includes neurologic and medical conditions often associated with catatonic syndrome.^17,18

In a retrospective study, Kaplan¹² assessed clinical presentations and reasons for diagnostic delay in 23 adults eventually diagnosed with NCSE. Presenting symptoms included:

• confusion, agitation, aggressive behavior
  
• lethargy, mutism, verbal perseveration, echolalia
  
• delirium, blinking, staring, chewing or picking behaviors
  
• tremulousness or myoclonus
  
• bizarre behavior (inappropriate laughing, crying, or singing)
  
• rigidity with waxy flexibility
  
• delusions, hallucinations.
  

Clinicians mistook hallucinations and mood lability for a primary psychiatric condition in 7 patients, presumed catalepsy was psychogenic in 3 patients, and thought obtundation was caused by alcohol or drug intoxication in 4 cases.

A prospective study of 22 patients with NCSE found that 7 had a history of psychotic depression, schizophrenia, self-mutilation, bipolar disorder, or episodic severe aggression; 12 of 18 with ASE had a history of epilepsy, and 3 of 4 with CPSE had experienced seizures associated with cerebrovascular accident, right cerebral embolus, and thiazide-induced hyponatremia, respectively.¹⁶

 

Table 2

Differential diagnosis of NCSE

Metabolic disorders	Hypo/hyperglycemia, hypercalcemia, Addison’s disease, Cushing’s disease, uremia
Neurologic disorders	Stroke, CNS tumors, closed head trauma, transient global amnesia, seizures, inflammatory and infectious encephalopathies
Psychiatric disorders	Schizophrenia, mood disorders, catatonia, malignant catatonia, somatoform disorders, conversion disorder, Asperger’s syndrome, malingering
Toxic disorders	Toxic encephalopathy, neuroleptic malignant syndrome, serotonin syndrome, alcohol and sedative-hypnotic withdrawal, drugs (lithium toxicity, tricyclics, baclofen, tiagabine, overdose)
Source: Reference 17,18

NCSE in the elderly can be difficult to diagnose, especially in patients with comorbid severe medical illnesses and other confusional states.⁴CPSE with possible generalization is more common than ASE in the elderly. Hyperreligiosity, intermittent agitation, motor perseveration, ictal fear, catatonic signs, delusional preoccupation, and auditory and visual hallucinations have been observed during NCSE in the elderly and misdiagnosed as primary psychiatric conditions.

Cerebrovascular disease, tumors, and trauma are the most common causes of late-life NCSE.^4,19 De novo NCSE occasionally presents:

• after benzodiazepine withdrawal
  
• with neuroleptic, tricyclic antidepressant, or lithium treatment^10,16
  
• with metabolic abnormalities and nonpsychotropic medications.¹⁰
  

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

Domain	Features
Cognitive changes	Prolonged confusion, executive dysfunction, obtundation, attention/memory difficulties, lack of initiative, perseveration, stupor
Speech	Poverty of speech with monosyllabic answers, verbal perseveration, echolalia, palilalia, aphasia, paraphasic errors, confabulation, mutism
Affective	Prolonged fear, affective indifferent state with blank facial expression, hypomania, psychotic depression, inappropriate laughing and crying, anxiety states
Psychosis	Visual, auditory and cenesthetic hallucinations, delusions
Impulse control	Hostility, agitation, violence, groping, genital manipulation, picking, posturing
Others	Catatonic signs, autonomic disturbances
Source: References 5,7-9,12,15-17,20-23

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 summarized 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.

Table 4

EEG findings that support a clinical diagnosis of NCSE

Clear-cut criteria
Frequent or continuous focal seizures, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution
Frequent or continuous generalized spike wave discharges:
in patients without history of epilepsy in patients with epilepsy, when discharges show significant changes in intensity or frequency compared with baseline EEG
Periodic lateralized epileptiform discharges (“PLEDs”) or bilateral periodic epileptiform discharges (“biPEDs") occurring in patients with coma from generalized tonic-clonic status epilepticus (subtle SE)
Probable (equivocal) criteria
Patients with acute cerebral damage who also show frequent or continuous EEG abnormalities without previous similar findings
Patients with epilepsy who show frequent or continuous generalized EEG abnormalities and similar interictal EEG patterns but whose clinical symptoms suggest NCSE
Source: References 4,12-14,17

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

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.

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

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.

Nonconvulsive status epilepticus (NCSE) is marked by neurobehavioral disturbances that resemble primary psychiatric disorders. Mistaken diagnosis and delayed treatment increase the risk of neurologic damage, so recognizing NCSE symptoms early is important.

To help you make a timely diagnosis, this article describes:

• neuropsychiatric manifestations of NCSE
  
• how to narrow the differential diagnosis by reviewing clinical symptoms and using electroencephalography (EEG)
  
• techniques used to rapidly halt ictal activity.
  

Box

Triggers, neurologic symptoms

NCSE is an acute but treatable medical emergency that calls for assessing and supporting cardiac and respiratory function, monitoring vital signs, temperature reduction, and fluid replacement. Prognosis is usually good unless NCSE is associated with a serious medical illness (Box).^1-11

Many metabolic, neurologic, pharmacologic, and medical abnormalities can precipitate NCSE (Table 1). The most common causes are hypoxia/anoxia, stroke, infection, subtherapeutic antiepileptic levels, alcohol and benzodiazepine intoxication/withdrawal, and metabolic abnormalities.^4,7,10,12

NCSE manifests as absence status epilepticus (ASE) or complex partial status epilepticus (CPSE). A generally accepted diagnostic definition is ≥30 minutes of behavioral change from baseline, with diagnostic EEG findings.^4,13 EEG is indispensable because the clinical manifestations of NCSE are predominantly behavioral, with minimal or no motor activity.

Table 1

Clinical factors that may precipitate NCSE

Medical	Recent infection, hyperventilation, trauma, menstruation, pregnancy, renal dialysis, postoperative period, sleep deprivation
Metabolic	Hypoparathyroidism, renal failure, hyper/hyponatremia, hyper/hypoglycemia, hypocalcemia
Neurologic	Mental retardation, dementia, stroke
Pharmacologic	Low serum levels or abrupt discontinuation of anticonvulsants, alcohol intoxication/withdrawal, benzodiazepine withdrawal lithium and neuroleptic use, psychotropic overdose
Source : References 9,10,12,16

ASE, a primary generalized process, is characterized by confusion or diminished responsiveness; it may be associated with occasional blinking or other minor motor activity and can last for hours to days. It usually occurs in patients with known epilepsy, particularly absence seizures.

ASE is reported primarily in children, although de novo cases have been described in elderly patients with no history of epilepsy.^10,14

CPSE is usually associated with a history of focal epilepsy and vascular disease. CPSE has a focal onset, with subsequent secondary generalization. Onset is usually temporal in origin but also can be extratemporal.

Patients with CPSE often cycle between an “epileptic twilight state” with confusion and complete unresponsiveness with stereotyped automatisms. It can present with marked behavioral fluctuation or a change in mental status and is generally followed by a prolonged postictal state.^4,7,13-15 Several NCSE cases have occurred in patients with no history of seizures.^9,10,16

Historically, CPSE was reported to be less common than ASE, but this misconception was most likely caused by failure to recognize CPSE’s clinical presentation and rapid generalization on EEG.^7,15

Neuropsychiatric features

Patients with NCSE may be referred for evaluation of an array of behavioral changes commonly seen in psychiatric practice. The differential diagnosis is extensive (Table 2) and includes neurologic and medical conditions often associated with catatonic syndrome.^17,18

In a retrospective study, Kaplan¹² assessed clinical presentations and reasons for diagnostic delay in 23 adults eventually diagnosed with NCSE. Presenting symptoms included:

• confusion, agitation, aggressive behavior
  
• lethargy, mutism, verbal perseveration, echolalia
  
• delirium, blinking, staring, chewing or picking behaviors
  
• tremulousness or myoclonus
  
• bizarre behavior (inappropriate laughing, crying, or singing)
  
• rigidity with waxy flexibility
  
• delusions, hallucinations.
  

Clinicians mistook hallucinations and mood lability for a primary psychiatric condition in 7 patients, presumed catalepsy was psychogenic in 3 patients, and thought obtundation was caused by alcohol or drug intoxication in 4 cases.

A prospective study of 22 patients with NCSE found that 7 had a history of psychotic depression, schizophrenia, self-mutilation, bipolar disorder, or episodic severe aggression; 12 of 18 with ASE had a history of epilepsy, and 3 of 4 with CPSE had experienced seizures associated with cerebrovascular accident, right cerebral embolus, and thiazide-induced hyponatremia, respectively.¹⁶

 

Table 2

Differential diagnosis of NCSE

Metabolic disorders	Hypo/hyperglycemia, hypercalcemia, Addison’s disease, Cushing’s disease, uremia
Neurologic disorders	Stroke, CNS tumors, closed head trauma, transient global amnesia, seizures, inflammatory and infectious encephalopathies
Psychiatric disorders	Schizophrenia, mood disorders, catatonia, malignant catatonia, somatoform disorders, conversion disorder, Asperger’s syndrome, malingering
Toxic disorders	Toxic encephalopathy, neuroleptic malignant syndrome, serotonin syndrome, alcohol and sedative-hypnotic withdrawal, drugs (lithium toxicity, tricyclics, baclofen, tiagabine, overdose)
Source: Reference 17,18

NCSE in the elderly can be difficult to diagnose, especially in patients with comorbid severe medical illnesses and other confusional states.⁴CPSE with possible generalization is more common than ASE in the elderly. Hyperreligiosity, intermittent agitation, motor perseveration, ictal fear, catatonic signs, delusional preoccupation, and auditory and visual hallucinations have been observed during NCSE in the elderly and misdiagnosed as primary psychiatric conditions.

Cerebrovascular disease, tumors, and trauma are the most common causes of late-life NCSE.^4,19 De novo NCSE occasionally presents:

• after benzodiazepine withdrawal
  
• with neuroleptic, tricyclic antidepressant, or lithium treatment^10,16
  
• with metabolic abnormalities and nonpsychotropic medications.¹⁰
  

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

Domain	Features
Cognitive changes	Prolonged confusion, executive dysfunction, obtundation, attention/memory difficulties, lack of initiative, perseveration, stupor
Speech	Poverty of speech with monosyllabic answers, verbal perseveration, echolalia, palilalia, aphasia, paraphasic errors, confabulation, mutism
Affective	Prolonged fear, affective indifferent state with blank facial expression, hypomania, psychotic depression, inappropriate laughing and crying, anxiety states
Psychosis	Visual, auditory and cenesthetic hallucinations, delusions
Impulse control	Hostility, agitation, violence, groping, genital manipulation, picking, posturing
Others	Catatonic signs, autonomic disturbances
Source: References 5,7-9,12,15-17,20-23

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 summarized 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.

Table 4

EEG findings that support a clinical diagnosis of NCSE

Clear-cut criteria
Frequent or continuous focal seizures, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution
Frequent or continuous generalized spike wave discharges:
in patients without history of epilepsy in patients with epilepsy, when discharges show significant changes in intensity or frequency compared with baseline EEG
Periodic lateralized epileptiform discharges (“PLEDs”) or bilateral periodic epileptiform discharges (“biPEDs") occurring in patients with coma from generalized tonic-clonic status epilepticus (subtle SE)
Probable (equivocal) criteria
Patients with acute cerebral damage who also show frequent or continuous EEG abnormalities without previous similar findings
Patients with epilepsy who show frequent or continuous generalized EEG abnormalities and similar interictal EEG patterns but whose clinical symptoms suggest NCSE
Source: References 4,12-14,17

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

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.

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

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.