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Seizures are reported in about one third of patients with severe liver disease in association with acute or chronic liver failure. Majority of the seizures are of focal type. Occasionally generalized tonic clonic seizures are seen when there is ethanol withdrawal. Not much is known about Ictal blinking (IB) in severe liver disease. IB is rare form of seizures and was reported in severe liver disease recently from this institute. Oculogyric crisis (OGC) is rarely reported in relation to the severe liver disease. OGC was also noted first time in our Intensive Care Unit.
Methods
At the institute of liver and biliary sciences (ILBS) data on patients with IB and OGC was analyzed from October 2018 to January 2023 (52 months). All the patients had video electroencephalograph (video-EEG) recording after proper permission/consent. The patients were followed up later for the course of the illness.
Results
16 (12M: 4F) patients were seen. Majority 12 (75 %) were IB and 3 OGC.EEG was abnormal in nine (75.0%) of IB patients. Brain imaging had nonspecific findings. Outcome was based on the severity and recovery of the underlying liver disease.
Conclusions
Unusual facial movements in form of IB and OGC are reported, which are most of the time missed. This report highlights the importance of recognition of these events and proper in time management to improve the outcome.
By definition the seizure is confined to the eye lids. There may be eye deviation or involvement of orbicularis oculi without spread to other parts of the body. There is associated loss of consciousness.
IB mechanism is unknown. Twelve patients with IB were seen in last four years. Brain imaging was nonspecific and EEG abnormality was seen in about three fourth of these patients.
Oculogyric literally means pertaining to rotation of eye ball. When oculogyric crisis is used it pertains to tonic upward gaze of eye balls with retained consciousness.
Three patients with OGC and one with jaw seizure were seen.
Material and Methods
The patients with liver failure in acute or chronic liver disease with or without hepatic encephalopathy admitted in various intensive care units (ICUs) like liver ICU, surgical ICU, high dependency unit (HDU) and liver transplant ICU of the institute of liver and biliary sciences (ILBS) formed the subjects of the study. Also included were four patients with ictal blinking after liver transplant. These four were admitted in liver transplant ICU. All patients had history of hepatic encephalopathy (HE) in the past. IB and OGC were diagnosed on the defined criteria.
The patients with IB and OGC had detailed neurological examination. Usually, neurological opinion was sought when hepatologists/hepatobiliary surgeons/attending doctors could not explain reasons for unexplained unresponsiveness or obtundation in the patient. During neurological examination when IB or OGC was noted, video recording was done on smart phones after proper permission from the close relatives of the patient. All the patients had EEG, computerized tomography (CT) or magnetic resonance imaging (MRI) brain and baseline blood work up like electrolytes and ammonia. Routine half an hour EEG was recorded usually after managing the IB. Only two patients had EEG at the time of IB. Only three patients had a repeat follow up EEG. Cerebrospinal fluid (CSF) examination was not done in any patient as it was not indicated clinically and there was associated coagulopathy in some. All the patients received stat dose of 5 mg midazolam intravenous followed by levetiracetam 1 G intravenous infusion. Levetiracetam was continued in two divided doses 12 hours later (usually 750mg twice a day). All the patients were followed up till discharge or death.
The patients with OGC were not given any particular medications. A drug history and current medications were screened which could result OGC. They were followed till recovery from OGC. One patient admitted for management of chronic liver disease and history of HE, was diagnosed as jaw seizure. His work up for HE in this admission was negative.
Results
From October 2018 to January 2023 (52 months) 16 patients (12M: 4F) with unusual facial movements were seen at ILBS. IB was the most common and was seen in 12 (75%) patients. IB was seen in severe liver disease patients irrespective of underlying etiology for liver disease. Table 1, Table 2 Four patients of IB were post liver transplant (LT), two in HD, one in SICU, and rest in liver ICU. IB in post LT patients was seen from day 2 to day 45 (19.2 days mean). At the time of IB in LT patients, serum electrolytes, ammonia and tacrolimus levels were normal. Typical IB is seen in video 1 (supplementary file). A static photo from video is seen in (a). All 12 IB patients had no previous history of seizures. 9 of the 12 patients with IB had abnormal EEG. Figure 1. Abnormalities were mainly over bifrontal and frontotemporal regions. Follow up EEGs were done in 3 patients only and the EEGs were normal. Brain imaging had nonspecific findings as seen in the table 1. Only one patient with OGC had micro hemorrhages. OGC was seen in three patients. (Video 2 supplementary file). A static photo from video(b). In 3 OGC patients, two had nonalcoholic steatosis hepatitis (NASH) and cirrhosis while 3rd patient had acute liver failure of unknown etiology. (Table 3). These patients were not on drugs known to produce OGC other than propofol anesthesia in two. One of them died due to the liver disease. This patient had NASH with cirrhosis and died of multiorgan failure. However, 4 days before death his OGC was not seen in him.OGC lasted from one to 7 days in these three patients. EEG did not reveal seizures in any of them. Patient number 1 underwent emergency live liver donor transplant and was discharged from hospital recently.
Table 1shows clinical features, investigations and outcome of the patients with ictal blinking with hepatic encephalopathy.
S No
Age/sex
Diagnosis
Seizure Semiology
EEG
MRI/CT brain
Treatment
Outcome
Transplant
Other Medications
1
48/M
Cirrhosis liver, cryptogenic
Ictal Blinking, orbicularis oculi post LT
Normal
CT volume loss
Mdz., Lev
Seizure free
Deceased LT
Methyl Prednisolone., Basilumab,Tacrolimus
2
56/M
Cirrhosis Hep B/C
Ictal Blinking post LT
Frontotemporal spikes, generalization
MRI normal
Mdz., Lev
Seizure free
Live donor LT
Methyl prednisolone., Tacrolimus
3
42/M
Cirrhosis, Ethanol related
Ictal Blinking
Periodic spikes, burst suppression
CT volume loss
Mdz. Lev., Lac.
Died of sepsis, DIC
No
No
4
9y/M
Acute liver failure, undetermined
Ictal Blinking with eyes deviation post LT
Normal
MRI normal
Mdz. Lev.
Seizure free
Live donor LT
Methyl prednisolone., Tacrolimus
5
50/M
Cirrhosis Ethanol related
Blinking
Periodic spikes, focal discharges
CT normal
Mdz. Lev., Lac.
Died of sepsis, DIC
No
No
6
55/F
Cirrhosis, scleroderma, disseminated tuberculosis
Ictal Blinking,
Focal seizure discharges
CT normal
Mdz., Lev.
Died of sepsis/disseminated tuberculosis
No
No
7
52/M
Cirrhosis Ethanol related
Ictal Blinking and orbicularis oculi
Generalized spike discharges
MRI/CT Subdural hematoma
Lev
Seizure free
No
Propofol,
8
51M
Cirrhosis Cryptogenic
Ictal Blinking and right forearm jerks
Generalized spike discharges
MRI/CT normal
Lev
Seizure free
Live donor LT
None
9
60 M
Ethanol and Cirrhosis
IB and left fore arm
Focal seizures
CT volume loss
Lev
Seizure free
No
Liver related
10
64 F
NASH & Cirrhosis
IB
Ictal EEG
CT normal
Mdz Lev
Seizure free
No
Liver related
11
65 M
NASH & Cirrhosis
IB
Focal slowing
CT volume loss
Lev
Seizure free
No
Liver related
12
54 F
Cholangiocarcinoma with metastasis, secondary biliary Cirrhosis
IB
Multifocal seizures
CT/MRI microhemohrages, no metastases
Lev,Phenytoin sodium,
died
No
Anticancer medications
M-male, F- female, B/C- hepatitis B and C,IB-ictal blinking, NASH-nonalcoholic steatosis hepatitis, CT-computerized tomography,MRI-Magnet resonance imaging,Mdz.-Midazolam,Lev.-Levetiracetam, Lac.-Lacosamide,DIC-disseminated intravenous coagulopathy,LT-Liver transplant. Please note patient number 1,2,4,8 had liver transplant.
Figure 1EEG at the time of blinking in 64-year NASH with cirrhosis lady shows multifocal spikes (single arrows) and generalized seizure discharges (double arrows).
52-year-old lady with cryptogenic acute liver failure with oculogyric crisis. There is tonic up-gaze with reduced blinking and contracted frontalis muscle. The patient is conscious, she closes eyes on seeing the object from left side
One patient was seen with jaw seizures. He was a 62 years old male patient with chronic liver disease with NASH and had history of ethanol intake as well. He had history of HE in past. He was admitted four times in past three months at a peripheral hospital with drowsiness thought to be hepatic encephalopathy. However, his work up was always within normal range (serum ammonia not raised). When he was admitted in this hospital, the laboratory work could not explain his frequent encephalopathy like illness. The history review suggested he would get involuntary movements of jaw lasting few minutes. At this time, he would become unresponsive without any tonic clonic movements or loss of posture or tone. The movements would happen even in sleep. His examination was normal. Video recorded by wife was seen (video 3 in supplementary file). MRI brain and EEG were done. His EEG was abnormal (figure 2) and brain imaging was normal. He was started on levetiracetam and in about half a day his sensorium improved and he was discharged next day. He was seen on follow up in the clinic and was doing well.
Figure 2Interictal EEG of 62 years NASH with cirrhosis patient with jaw seizures shows bifrontal sharp waves, sharp and slow wave discharges.
Blinking is usually bilateral but can involve only one eye. During blinking there is impairment to loss of consciousness. Bilateral blinking has less localizing value and has been seen in lesions involving frontal, temporal, occipital lobes, cerebellum and fourth ventricular mass. 2,3,4,5 Unilateral blinking has more localization value, indicating contralateral cortical lesion.
Since recognition of this entity (IB) more cases are picked up by the treating team, residents and other staff. Amongst 12 patients of IB, four were post LT. IB was seen in them from day 2 to 45 days (19.2 days mean) after liver transplant. They all were extubated and doing well. The duty doctors in liver transplant ICU noted them in deranged sensorium. All metabolic work up including ammonia were normal. IB was diagnosed on neurological examination. What is the mechanism of IB in severe liver disease with or without HE? It cannot be explained on one factor alone. Underlying reasons seem to be multifactorial like ammonia toxicity, brain edema, neurotransmitter imbalance, toxic aromatic amino acids accumulation, tacrolimus and anesthetic agents.
But only three patients were on tacrolimus post liver transplant and the serum levels were in therapeutic range. Fourth LT patient and rest 8 patients also did not receive tacrolimus. In nine out of 12 (75%) IB patients, EEG was abnormal. Usually EEGs were performed after the initial treatment of IB at the time of diagnosis, other than two patients who had EEGs before treatment. Most of the time seizure discharges were from frontotemporal region. However multifocal and generalized seizure discharges were also seen (Figure 1). Brain imaging was nonspecific in our patients. The abnormalities seen were brain atrophy, subdural hematoma in one, and few micro hemorrhages etc.
The seizures responded very well to levetiracetam alone, though most received midazolam stat dose at the time of diagnosis. Five of 12 patients died due to the underlying serious liver disease and HE and not because of IB. With the features as described in IB in our patients there is no other diagnosis. However any person with fast blinking rate, one needs to differentiate from blepharospasms and tics. In both these conditions, consciousness is not lost and the person can control them at will.
Any part of the central nervous system (cortex, white matter, basal ganglia, brainstem, cerebellum spinal cord) can be involved in liver disease both acute and chronic type.
Two of our three OGC patients had NASH with cirrhosis. Third case had acute liver failure of unknown etiology. This patient with acute liver failure underwent emergency LT. (Table 3). OGC is seen in association with large number of conditions. These are genetic, neurometabolic, vascular, infective, drugs,dystonia and demenetia.
Gold DR. Eye movement disorders: Conjugate gaze abnormalities [Internet]. In: Liu GT, Volpe NJ and Galetta SL (des) Liu, Volpe and Galetta’s Neuro-Ophthalmology. 3rd de. Elsevier.2019[cited Mar 26,2020],pp 549-584,.https://www.sciencedirect.com/acience/article/pii/B978032334044100016X(accessed July 27,2020
Gold DR. Eye movement disorders: Conjugate gaze abnormalities [Internet]. In: Liu GT, Volpe NJ and Galetta SL (des) Liu, Volpe and Galetta’s Neuro-Ophthalmology. 3rd de. Elsevier.2019[cited Mar 26,2020],pp 549-584,.https://www.sciencedirect.com/acience/article/pii/B978032334044100016X(accessed July 27,2020
Gold DR. Eye movement disorders: Conjugate gaze abnormalities [Internet]. In: Liu GT, Volpe NJ and Galetta SL (des) Liu, Volpe and Galetta’s Neuro-Ophthalmology. 3rd de. Elsevier.2019[cited Mar 26,2020],pp 549-584,.https://www.sciencedirect.com/acience/article/pii/B978032334044100016X(accessed July 27,2020
Gold DR. Eye movement disorders: Conjugate gaze abnormalities [Internet]. In: Liu GT, Volpe NJ and Galetta SL (des) Liu, Volpe and Galetta’s Neuro-Ophthalmology. 3rd de. Elsevier.2019[cited Mar 26,2020],pp 549-584,.https://www.sciencedirect.com/acience/article/pii/B978032334044100016X(accessed July 27,2020
Two of our patients (one acute liver failure and second chronic liver disease) were on propofol. However, third patient did not receive propofol. Recovery of OGC on improvement of ALF could be a point in favor of liver disease as the causative factor in our first patient. In this patient OGC lasted for four days. Propofol was not used in the third patient. There was no history of other drug intake prior to hospitalization resulting OGC in any of our patients. Further OGC developed in hospital in all of them (2 after intubation and one without intubation). One has to exclude seizures in OGC. A bedside examination and EEG help to rule this out. These patients are conscious and a simultaneous EEG is normal other than effect of underlying encephalopathy. All the three patients had OGC settled, after one to 7 days. (Photos a1b1).
Jaw seizure in liver disease with HE is not reported before. Since seizures are reported in one third of, HE patients,
isolated jaw seizure may be seen in them occasionally. Bruxism should be considered in differential diagnosis of jaw seizure. In bruxism there is continuous teeth grinding due to the excessive use of masseter muscles in sleep. The patient’s video did not reveal teeth grinding at all. (Video 3 supplementary file). There were no masseter muscle contractions and artifacts noted during EEG recording. The muscle contractions produce a lot of muscle artifacts on EEG which were not seen and EEG had revealed seizure discharges (Figure 2).
Limitations
The cohort of this case series is quite heterogenous and includes patients with acute liver failure, decompensated cirrhosis and post LT patients. Continuous EEG monitoring was not done. Neurotransmitter estimation and cerebrospinal fluid study was not done. May be in future study, one can find the triggering mechanism for these unusual facial movements.
Conclusions
IB, OGC, jaw seizure are reported for the first time in severe liver disease, sometimes also in patients with present or past hepatic encephalopathy. When there are no clear reasons to explain unresponsiveness on liver disease, one must look for seizures particularly IB in these patients, which can produce obtundation/unresponsiveness. On simple observation of the face for few minutes, one can make the diagnosis.
Conflict Of Interest
There is no conflict of interest.
Acknowledgement
The authors are thankful to Sadam H Bhat, dept of Molecular and Cellular Medicine, ILBS Hospital Delhi, India and Dr Shashikant Koul for software work in the manuscript.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
Gold DR. Eye movement disorders: Conjugate gaze abnormalities [Internet]. In: Liu GT, Volpe NJ and Galetta SL (des) Liu, Volpe and Galetta’s Neuro-Ophthalmology. 3rd de. Elsevier.2019[cited Mar 26,2020],pp 549-584,.https://www.sciencedirect.com/acience/article/pii/B978032334044100016X(accessed July 27,2020
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