Accepted Manuscript

Title: Status epilepticus in cirrhotic patients: how to avoid

misdiagnosis in patients with hepatic encephalopathy

Author: Marika Rudler Clémence Marois Nicolas Weiss

Dominique Thabut Vincent Navarro

PII: S1059-1311(16)30331-4
DOI: http://dx.doi.org/doi:10.1016/j.seizure.2016.12.011
Reference: YSEIZ 2873

To appear in: Seizure

Received date: 12-7-2016

Revised date: 7-12-2016
Accepted date: 15-12-2016

Please cite this article as: Rudler Marika, Marois Clémence, Weiss Nicolas, Thabut
Dominique, Navarro Vincent.Status epilepticus in cirrhotic patients: how to avoid
misdiagnosis in patients with hepatic encephalopathy.SEIZURE: European Journal of
Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.12.011

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 Status Epilepticus in Hepatic 1
Encephalopathy
Status epilepticus in cirrhotic patients: how to avoid misdiagnosis in patients with

hepatic encephalopathy

Marika Rudler* (1, 2), Clémence Marois* (1, 3), Nicolas Weiss (1, 3, 4),

Dominique Thabut (1, 2), Vincent Navarro (4,5).

For the Brain-Liver Pitié-Salpêtrière Study Group (BLIPS)

1 : Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière

Charles Foix, Paris, France

2 : Unité de Soins Intensifs d’Hépatologie, Service d’Hépato-Gastroentérologie, Groupe

Hospitalier Pitié-Salpêtrière Charles Foix, Assistance Publique-Hôpitaux de Paris, Paris,

France

3 : Unité de Réanimation Neurologique, Fédération de Neurologie 1, Pôle des maladies du

système nerveux, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Assistance Publique-

Hôpitaux de Paris, Paris, France

4 : Institut de Neurosciences Translationnelles de Paris, Institut-Hospitalo-Universitaire-A-

Institut du Cerveau et de la Moelle (IHU-A-ICM), Paris, France

5 : Sorbonne University, UPMC Univ. Paris 06, F-75005, Paris, France ; AP-HP, GH Pitie-

Salpêtrière-Charles Foix, Epilepsy Unit and Department of Clinical Neurophysiology ; Institut

du Cerveau et de la Moelle (ICM ; INSERM UMRS1127, CNRS UMR7225, UPMC) F-75013,

Paris, France

*: Equally contributing authors

 Status Epilepticus in Hepatic 2
Encephalopathy
Corresponding author:
Dr Marika RUDLER
Unité de Soins Intensifs d’Hépatologie
Groupe Hospitalier Pitié-Salpêtrière Charles Foix
Tel : 33 (0)1.42.16.14.54
Fax: +33(0)1.42.16. 10.08
Mail: marika_rudler@yahoo.fr

Key bullet points:

Status epilepticus (SE) in cirrhotic patients is a rare but severe situation.

Hepatic encephalopathy may present as SE.

Some anti-epileptic drugs may aggravate HE.

Misdiagnosis of SE was made in 15% of cases in our series.

A joint review of the patients by neurologists and hepatologists could reduce errors in diagnosis.

We confirm that we have read the Journal’s position on issues involved in ethical publication

and affirm that this report is consistent with those guidelines.

Abstract

Purpose: Status epilepticus (SE) in cirrhotic patients is a rare but severe situation. Diagnosis

may be difficult in emergency, especially when patients present with hepatic encephalopathy

(HE). Misdiagnosis must be avoided since some anti-epileptic drugs aggravate HE. In this

retrospective study, we therefore assessed the frequency of SE in cirrhotic patients, evaluated

the accuracy of diagnosis and determined rates of mortality.

 Status Epilepticus in Hepatic 3
Encephalopathy
Method: We reviewed data from all patients hospitalized from 2005-2013 in the Hepatology

ICU for complications of cirrhosis with an initial diagnosis of SE. We attempted to reach a

consensus decision on a possible diagnosis of SE in reviews of EEG traces and medical records

by an expert electrophysiologist, a hepatologist and a neurologist.

Results: An initial diagnosis of SE was made for 20 cirrhotic patients. Critical review suggested

that 15 of these patients were correctly diagnosed with true SE. However, initial diagnoses

may have been mistaken for at least 3 patients, who presented clinical and electrical signs of

HE without evidence for SE. Overall, we estimated a prevalence of 0.7% for SE in cirrhotic

patients (15 of 2010 patients admitted to our ICU) in our series. In-hospital mortality was of

73%. In the 12 months after the SE episode, mortality was 87%.

Conclusion: As SE may be misdiagnosed in patients with cirrhosis, a joint review of the patients

by neurologists and hepatologists could reduce errors in diagnosis.

Abbreviations:

Status epileptic: SE

Hepatic encephalopathy: HE

Electroencephalogram : EEG

Intensive Care unit: ICU

Model for End-Stage Liver Disease: MELD

Key words: cirrhosis, status epilepticus, hepatic encephalopathy

Introduction

Diverse neurological comorbidities and complications are common in patients with liver

cirrhosis [1][2]. One rare, but serious, complication is status epilepticus (SE) which is difficult to

diagnose and to treat.

 Status Epilepticus in Hepatic 4
Encephalopathy
SE is defined as a continuous clinical and/or electrographic seizure or recurrent seizure activity

without recovery for at least 30 minutes [3] [4]. SE can be classed as convulsive (CSE) or non-

convulsive (NCSE). CSE includes tonic–clonic SE, tonic SE, clonic SE and myoclonic SE. In

NCSE, defined by ictal electroencephalographic (EEG) discharges, consciousness may be

[5]
impaired without motor manifestation . The incidence of SE in general population has been

estimated from 10 (in Switzerland) to 41 patients (in the United States) per year per 100,000

people [6][7][8]. Estimates of mortality range from 3.45% to 33% [9][10][11][12].

SE may be difficult to diagnose in patients with hepatic encephalopathy (HE). Thus, HE may

be misdiagnosed as NCSE in patients with confusion, stupor or coma and lack of overt (tonic,

clonic, tonic-clonic and myoclonic) motor manifestations [2] [13][14]. Abnormal movements, such

as asterixis, irregular tremor or multifocal myoclonus, are usually associated with HE in

cirrhotic patients. These motor features may additionally cause the misdiagnosis as CSE, in

patients with HE. Therefore, HE may be misinterpreted as SE in cirrhotic patients, and

prescription of antiepileptic drugs may aggravate HE [15] .The best way to avoid such difficulties

is to perform an EEG recording which provide objective parameters to distinguish SE from HE

[16]
.

This study therefore aimed to assess: (1) the frequency and the mortality of SE in cirrhotic

patients, and (2) the proportion of confirmed SE in cirrhotic patients previously diagnosed with

SE, by critical, retrospective analyses of medical reports and EEG records.

Methods

This retrospective study was conducted with data from patients of the tertiary Intensive Care

unit (ICU) of Hepatology and Gastroenterology in La Pitié-Salpêtrière Hospital, Paris, France.

Patients
 Status Epilepticus in Hepatic 5
Encephalopathy
We reviewed files of patients hospitalized in the ICU, consecutively from January 2005 until

December 2013. The hospital coding system (PMSI: medicalization program of information

system) allowed the identification of patients with a diagnosis of both cirrhosis and SE.

Clinical and biological data

We reviewed age and gender of patients as well as the natural history of their cirrhosis

(aetiology, presence of complications such as hepatocellular carcinoma, oesophageal varices,

[17]
ascites). Cirrhosis severity was evaluated by the Child-Pugh classification , a score that

includes biological (prothrombin time, albumin, bilirubin) and medical parameters (HE,

ascites). There are 3 classes, i.e. A, B and C, C reflecting the most severe situation. The

standardized United Network for Organ Sharing formula was used to calculate a score of the

Model for End-Stage Liver Disease (MELD): 0.957 x ln (creatinine [mg/dL]) + 0.378 x ln

(bilirubin [mg/dL]) + 1.120 x ln (INR) +0.6431 [18]. Neurological status at admission, including

clinical signs of HE, was reviewed. Causes of admission, including alcohol withdrawal, or

intoxication, gastrointestinal bleeding, sepsis, hypoglycaemia, acute alcoholic hepatitis (AAH),

acute kidney injury, were assessed as were any complications during admission. Seizure

descriptions and evolution after treatment were obtained. Brain CT-Scan, MRI and EEG records

performed during hospitalisation were retrieved. The duration of hospitalisation, and evolution

of patients after release from hospital including details on mortality if relevant were also

collected.

Neurological assessment

Medical records from identified patients were assessed by an expert hepatologist, an expert

neurologist and an expert electrophysiologist. Diagnoses were classed as “true SE”, “false SE”

or “uncertain SE”. A “true SE” was defined by a clinical description of a typical motor SE, with
 Status Epilepticus in Hepatic 6
Encephalopathy
predisposing factors and / or a compatible EEG. A “false SE” was defined by an atypical clinical

description with no or atypical EEG traces. In the absence of sufficient clinical and EEG data a

diagnosis of “uncertain SE” was retained

A motor SE was defined by at least 5 minutes of myoclonic, tonic or clonic or tonico-clonic

movements, generalized (bilateral and symmetrical), or partial (hemicorporal or focal). A motor

[19] [20]
SE was not always associated with a loss of consciousness . Pro-epileptic precipitating

factors included alcohol or treatment withdrawal, biological disorders including abnormal

sodium level and hypoglycaemia, or brain imaging evidence for potentially epileptogenic

lesions.

Ictal or interictal EEG activities were used as evidence for SE. Interictal activities were defined
[21]
according to Noachtar et al Ictal events were defined according to the unified EEG

terminology and criteria for NCSE [22] [23].

The EEG pattern specific to HE was defined as a slow activity (2–3Hz) maximal over anterior

regions, with fluctuating triphasic waves (TW) of moderate to high amplitude with 2-4

negative-positive-negative phases that typically occurred repetitively at 2 per second. The EEG

pattern associated with benzodiazepines (BZD) was defined as a diffuse 13-35 Hz rhythmic

activity [24].

Statistical analysis

Quantitated data were described with a mean and range, and qualitative variables with a number

or percentage. Contact was lost with some patients. They were counted as alive at the time of

their last visit. Statistical analysis was performed with NCSS software.
 Status Epilepticus in Hepatic 7
Encephalopathy
Results

Patient’s characteristics

2010 patients with cirrhosis were hospitalized in the ICU from 2005 until 2013. Table 1

summarizes characteristics for the 20 patients (1%) initially diagnosed with a SE. 14 were male

and 6 female and median age was 58 years [range 39-78]. 16 of these patients were classified

as Child-Pugh C, with a median MELD of 24 [9-40]. No patient had a previous epileptic history,

5 had a history of HE, and 16 patients showed clinical signs of HE, from asterixis to coma,

during their stay.

Categorisation as true, false or uncertain SE

Clinical data were available for all patients. Table 2 describes EEG traces, obtained for 13

patients. Table 3 gives clinical, biological and radiological pro-epileptic factors as well as

descriptions of motor symptoms. Table 4 presents final diagnoses after expert review of clinical

and EEG data. Interictal (n=2) or ictal epileptic activity (n=6) was detected in EEG records

from 8 patients. Clinical symptoms of SE were apparent in 7 of these patients.

An EEG pattern suggestive of HE was recorded from 6 patients and was accentuated by

auditory stimulation in 2 of them. Patients with isolated changes in consciousness, without

concomitant epileptic activity on the EEG, no motor sign of SE or proepileptic predisposing

factor were classed as false SE (n=3).

EEG traces showed a BZD pattern with no epileptic feature in 2 patients. These patients were

classed as true SE since they both have showed typical ictal clinical symptoms.

EEG was not performed in 7 patients with a rapid adverse clinical evolution (3 of them died

less than a day after admission, or records could not be made as their condition worsened). Six

of them were classified as true SE since a clinically typical motor SE was observed together
 Status Epilepticus in Hepatic 8
Encephalopathy
with proepileptic precipitating factors. Two patients with non specific neurological symptoms

and no recorded EEG were classed as “uncertain SE”. Figure 1 shows typical EEG patterns and

their differences for SE and EH.

Overall, 15 of 20 patients were classed as true SE, 3 as false SE and 2 as uncertain. In

admissions to the ICU over the 13 years examined, the prevalence of SE in our cohort of

cirrhotic patients was estimated as 15 of 2010 patients (0.7%). Of the 15 patients with true SE,

12 showed generalised SE and 3 partial SE. Pro-epileptic factors were evident for 13 patients:

fever, 9; dysnatremia, 5; brain lesion, 3; alcohol withdrawal, 6; proepileptic drug, 3. In hospital

mortality for patients re-diagnosed with true SE was 73% (11 of 15) and 13 patients (87%) died

within a year of the SE.

 Status Epilepticus in Hepatic 9
Encephalopathy
Discussion

We have shown a low prevalence (0.7%) of SE in our cohort of cirrhotic patients admitted in

ICU. These patients had severe hepatic failure, and prognosis was poor with an intra-hospital

mortality of 73%, and a one-year mortality of 87%. About 15% of these patients were initially

misdiagnosed with SE, for two reasons. The first was effectively a clinical misdiagnosis.

Abnormal movements in patients with altered vigilance do not systematically indicate a seizure.

Myoclonic movements may have non-epileptic origins, notably in patients with metabolic

encephalopathies. Secondly EEG traces may be misinterpreted. Etiological diagnoses in

patients with altered consciousness and no obvious movement rely crucially on evidence from

EEG records. Faigle and al. already described the need for EEG evidence to properly diagnose
[25]
NCSE in patients with endocrine and metabolic encephalopathies . It may be difficult to

distinguish EEG records associated with a severe non-epileptic encephalopathy and a NCSE.

Lapergue et al describe such difficulties for patients with spongiform encephalopathy, sporadic

Creutzfeld Jakob disease (sCJD) which were first diagnosed with a NCSE [26]. Several features

may help the distinction. First, diffuse triphasic waves, maximal in anterior region, occurring

in 1.2 Hz rhythmic sequences, that usually decreased on auditory or nociceptive stimulation are

suggestive of an encephalopathy. Second, focal or generalised rhythmic activities with a spatio-

temporal organisation, such as progressive changes in amplitude and frequency that spread

progressively and that are not interrupted by auditory or nociceptive stimulation, are suggestive

of ictal activities. Such activities, during recordings of duration 20-30 minutes, provide strong

evidence for a SE.

Acute administration of rapidly acting antiepileptic drugs may generally help the diagnosis of

NCSE, when improvement of both clinical and EEG features is observed [22]. Nevertheless, in

the population of cirrhotic patients with hepatic encephalitis, we do not recommend this

therapeutical test at the time of a first EEG, because antiepileptic drugs, such as
 Status Epilepticus in Hepatic 10
Encephalopathy
benzodiazepines, may worse the encephalopathy, moreover a clinical improvement would be

difficult to identify in patients with altered consciousness related to HE and lastly

benzodiazepines may suppress EEG features (such as GPDs with triphasic morphology) of

non-epileptic encephalopathy.

Subacute encephalopathy with seizures in alcoholics (SESA syndrome) is another entity,

described in patients presenting with complex partial seizures or status, usually associated with

interictal LPDs [27].

We recognise some limits of this work. It was retrospective, based expert opinions of medical

records after the events. Possibly, some patients experienced a true initial SE, but epileptic

abnormalities were absent from subsequent EEG records. Possibly, some movements noted in

initial medical records did not result from epileptic activity. The form, appearance and duration

of movements in these patients together with a possible somatotopic distribution and

progression should be noted or preferably recorded, even by a smartphone. Close relations

between hepatologist and neurologists greatly facilitate good management of cirrhotic patients

with SE. Another defect of this study may be that it was based on patients admitted to an ICU,

and so tended to include patients with severe cirrhosis. The prevalence of SE may differ in other

subsets of cirrhotic patients, but it seems unlikely to be higher. Referral to an ICU seems likely

to be more probable for patients with neurological disorders such as SE. Our study was not

designed to specifically research for NCSE in cirrhotic patients with HE. A prospective study

is needed.

In conclusion, SE is a rare complication with a poor prognosis in patients with advanced

cirrhosis. In these patients, SE should be diagnosed with caution since some antiepileptic drugs

accentuate hepatic failure and can aggravate HE. SE diagnosis is best made from both clinical

observation and EEG features. It is crucial point for physicians in a hepatology ICU to be able

to distinguish non-epileptic from epileptic movement disorders. If patients show only changes
 Status Epilepticus in Hepatic 11
Encephalopathy
in vigilance, an EEG record, ideally coupled with a video recording, should be made by expert

neurophysiologists. Together with a full medical history and paraclinical exams, it represents

the best way to avoid misdiagnosis of a severe HE as a NCSE.

Authors ‘contribution:

Marika Rudler: study conception, management of patients, collection of data, writing the

manuscript

Clémence Marois: collection of data and writing the manuscript

Nicolas Weiss: Study conception, critical review of the data and the manuscript

Dominique Thabut: Study conception, critical review of the data and manuscript

Vincent Navarro: critical analysis of EEG, critical review of the manuscript

Financial/personal conflict of interest: the authors have nothing to disclose

None of the authors has any conflict of interest to disclose

Acknowledgments: This study was supported by the program “Investissements d’avenir”

ANR-10-IAIHU-06. The authors thank Richard Miles for comments on the manuscript.
 Status Epilepticus in Hepatic 12
Encephalopathy
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 Status Epilepticus in Hepatic 14
Encephalopathy
Figure 1

Comparison between EEG traces of SE and HE

Two EEG records, in bipolar montage, showing (A, SE) focal seizure from a status epilepticus

and (B, HE) an hepatic encephalopathy. The boxes at the top of the record summarize major

differences. The plain line indicates auditory stimulation, dotted lines indicate the beginning

and the end of the seizure. The arrow indicates specific waves.
 Status Epilepticus in Hepatic 15
Encephalopathy
Table 1: Baseline characteristics of patients

Total population
n = 20
Age (years) 58 ± 10
Male gender (%) 14 (70 %)
Etiology of cirrhosis
Viral 5 (25 %)
Alcohol consumption 15 (75 %)

Hepatocellular carcinoma 3 (15 %)

Ascites 14 (70%)
Previous HE 5 (25%)
Clinical HE 16 (80%)
Alcohol withdrawal 6 (30 %)
Gastrointestinal hemorrhage 8 (40%)
Sepsis context 8 (40%)
Hypoglycemia 0
PTT (%) 41 ± 22
INR 2,3 ±1,0
V factor (%) 44 ± 28
Platelet count (/mm3) 121600 ± 83800
Creatinine level (μmol/L) 94 ± 61
Albumin level (g/L) 28 ± 5
Bilirubin level (μmol/L) 134 ±125
AST level (U/L) 227 ± 343
ALT level (U/L) 89 ±97
Calcium level (mmol/L) 1,9 ± 0,2
Sodium level (mmol/L) 138 ± 6
CRP level (mg/l) 21 ± 23
Child Pugh score
A 2 (10 %)
B 2 (10 %)
C 16 (80 %)
MELD score 23 ± 10
Treatment with benzodiazepine drugs 20 (100%)

Data are mean ± SD or number (%)

HE hepatic encephalopathy
PTT prothrombin time
INR international standardized ratio
ALT alanine aminotransferase
AST aspartate aminotransferase
CRP C-reactive protein
MELD Model for End-Stage Liver Disease
 Status Epilepticus in Hepatic 16
Encephalopathy
Table 2: Detailed description of EEG pattern in each patient

Patient Detailed description of EEG (and final EEG diagnosis)

1 Generalized rhythmic high-voltage spike-and-waves, with a frontal predominance. No

reactivity to auditory stimulation (E).

2 Some distinctive spike-wave associated with some spiky lateralized periodic discharges
(LPDs) in the left fronto-temporal region: interictal epileptiform discharges (E).

3 Predominant beta rhythm (around 30 Hz) induced by benzodiazepine drugs

(BZD).
4 Slow and diffuse background activity, with continuous 2Hz GPDs with triphasic
morphology (TWs) (HE).

5 Diffuse, symmetric, continuous TWs, most prominent in the anterior region. No

reactivity to stimulation (HE).

6 Frontally predominant, bilateral and symmetrical PDs with triphasic morphology (HE).

7 Two or three successive well-organized seizures, located in central areas, consistently

more prominent in the right hemisphere (E).
In addition, generalized slow background, with diffuse delta waves (HE).

8 High frequency EEG activity (Beta rhythm induced by benzodiazepine drugs) (BZD).

9 Rhythmic sharp activity with a left central onset before a right central spread.

(E).
10 Periodic and paroxysmal fast spike activity, with right frontal location, and repeated
ictal rhythmic discharges with abrupt onset and termination (E).

11 Slow background activity, with spikes and sharp-waves prominent in the left side (E).

12 Slow and diffuse background activity, with continuous GPDs with triphasic
morphology (TWs) (HE).
In addition, generalized high-amplitude spiky rhythmic discharges (E).

13 Left occipito-temporal rhythmic ictal discharges (E), and diffuse TWs (HE)

E: epileptic pattern; PDs: periodic discharges; LPDs: lateralized periodic discharges; GPDs:
Generalized periodic discharges; TW : Triphasic waves; HE: Hepatic encephalopathy pattern,
BZD: benzodiazepine pattern
 Status Epilepticus in Hepatic Encephalopathy 17

Table 3 : Neurological description of movements and clinical, biological and radiological pro-epileptic factors

Patient Abnormal Clinical H OH Sodium Toxic / Brain CT scanner MRI

n° movements context E withdrawal abnorm treatment
aliy
1 Generalized Fever Y yes Diffuse oedema
convulsions e
s
2 Generalized Fever Y yes Hypernatremia Fronto-temporal
convulsions e hematoma
s
3 Generalized Y yes Hyponatremia cocaine Normal
convulsions Fever e naloxone
s
4 Arm myoclonus Y no Normal
e
s

5 No movements Y no Normal
e
s
6 Isolated head Y no nd
movements e
s
7 Generalized Fever Y yes Normal
convulsions e
s
8 Generalized N yes Normal
convulsions o
 Status Epilepticus in Hepatic Encephalopathy 18

9 Generalized Y no Hyponatremia Brain atrophy

convulsions Fever e
s
10 Focal motor Y yes Bilateral subdural
convulsions e hematoma
s
11 No description Y no nd
e
s
12 Abnormal Fever Y no Imipenem Normal
movements e
s
13 Generalized Fever N no Ciclospori Normal Manganese
convulsions o ne deposit
14 Hemibody Fever Y no nd Normal
clonus e
s
15 Generalized Y Lithium Normal
convulsions e
s
16 Generalized Fever Y nd Normal
convulsions e
s
17 Generalized N hypernatremia nd
convulsions o
18 Focal convulsions Y Multiple unilateral
e Hematoma
s
19 Generalized Y nd
convulsions e
s
 Status Epilepticus in Hepatic Encephalopathy 19

20 Focal seizure with N hyponatremia nd

secondary o
generalization

SE: status epilepticus

HE: hepatic encephalopathy
BZD: Benzodiazepine
nd : not done
OH : alcohol
Hyponatremia: natremia < 135 mmol/L
Hypernatremia : natremia >145 mmol/L
 Status Epilepticus in Hepatic Encephalopathy 20

Table 4: Final diagnosis according to experts’ reviews of clinical and electrophysiological data

Patient Available EEGs

n° Clinical SE E HE BZD Final diagnosis Type of SE
pattern pattern pattern (at onset)
1 Yes X TRUE SE GCSE
2 Yes Xint TRUE SE GCSE
3 Yes X TRUE SE GCSE
4 No argument X FALSE SE
5 No argument X FALSE SE
6 No argument X FALSE SE
7 Yes X X TRUE SE GCSE
8 Yes X TRUE SE GCSE
9 Yes X TRUE SE GCSE
10 Yes X TRUE SE Focal CSE
11 Uncertain Xint Uncertain SE
12 Yes X X TRUE SE GCSE
13 Yes X X TRUE SE GCSE
14 Uncertain Uncertain SE
15 Yes TRUE SE GCSE
16 Yes TRUE SE GCSE
17 Yes No EEG TRUE SE GCSE
18 Yes TRUE SE Focal CSE
19 Yes TRUE SE GCSE
20 Yes TRUE SE Focal CSE
EEG: electroencephalogram
E: epileptic; int : interictal epileptic activities
SE: status epilepticus; GCSE: generalised convulsive status epilepticus
HE: hepatic encephalopathy
BZD: Benzodiazepine