A middle aged man presented with seizures. For 4 days he had been feeling unwell with coryzal symptoms, frontal headache and dizziness. He had ‘not been himself’ for some months. He had no previous medical history and had never had a seizure before. The ambulance crew noted that he was confused and witnessed a generalised tonic-clonic seizure. On arrival in hospital he was severely agitated and uncooperative and received IV lorazepam.
He was not adequately protecting his airway, saturations were 100% on high flow oxygen, temperature was 37.8, his pulse was 88, BP 129/90mmHg, blood sugar was 7.7. Clinical examination did not reveal any abnormality except for diminished level of consciousness. A presumptive diagnosis of meningitis / encephalitis was made. His trachea was intubated, he received fluids, parenteral vitamins, IV ceftriaxone and acyclovir. A CT head (with contrast) was obtained and a lumbar puncture were normal. His blood tests, CXR, urinary toxicology screen, and ECG were non-contributory. Arterial blood gas analysis revealed changes consistent with being post ictal and then (whilst ventilated) normalised.
His sedation was weaned and once extubated he remained very drowsy, even 18 hours after his last sedation. A Glasgow Coma Score (GCS) was recorded at E1V1M5 (7/15). His pupils were equal and reactive, and he was moving all 4 limbs. Both plantar responses were down-going, and tone and reflexes were symmetrical. He had myoclonic jerking of his left hand but no rhythmical muscle activity was evident. To protect his airway he required reintubation of his trachea and re-institution of ventilation.
In addition to sedation with propofol and alfentanil he received therapeutic phenytoin. An electroencephalogram (EEG) performed on his second day, off sedation, revealed continuous periodic sharp and slow wave complexes at around 1Hz with intermittent high amplitude waves in the left temporal region and bursts of rhythmical activity in the right temporal region. At the time of the EEG he had some abnormal motor activity – continuous movement of his fingers and twitching of an eyelid and rhythmical jerking of both of his arms. An MRI of his brain was normal.
In this clinical context the EEG was interpreted as being consistent with encephalitis and non-convulsive status epilepticus. Phenobarbitone was started in addition to the phenytoin. Normothermia and normoglycemia was maintained. To improve the management of his non convulsive status we continuously monitored his cerebral electrical activity with a bispectral index (BIS) monitor and bitemporal EEGs. We targeted a burst suppression of 20-50%. Propofol was ineffective at reducing the BIS without causing limiting hypotension but midazolam was effective.
Further investigations did not further our search for the primary diagnosis. A further EEG was performed 24 hours later, off midazolam but whilst on 350mg/hr of propofol. He developed some rhythmical motor activity and his EEG revealed ongoing abnormal electric activity, consistent with continued non-convulsive status, which resolved in response to a bolus of propofol. A possible diagnosis of limbic encephalitis was considered and methylprednisolone (1g IV) was administered.
A repeat MRI showed increased abnormal signal changes in the amygdala and hippocampus, which is supportive of the diagnosis of limbic encephalitis.
Despite optimal medical treatment his EEG showed more severe and continued abnormal electrical activity. Thiopentone was added to his anti-seizure regime. By the 19th day from initial presentation multiorgan failure had developed. He required ventilation with high airway pressures and high inspired oxygen concentrations for lung injury due to ventilator associated pneumonia, vasoactive drugs to support his cardiovascular system through the associated sepsis, haemofiltration for renal failure and had ileus with failure of enteral feeding. There were still signs of seizure activity despite concurrent administration of propofol, midazolam, phenytoin, levetiracetam, phenobarbitone and sodium valproate. Supportive treatment was withdrawn following diagnosis of brain-stem death. His family did not permit a post mortem examination.
Encephalopathy is a broad term used to describe a disorder of brain function, which presents with depressed or altered level of consciousness lasting more than 24 hours, with lethargy, or change in personality. Sudden onset (acute) encephalopathy is usually due to drug or toxin exposure, metabolic abnormalities, or acute structural abnormalities of the cortex e.g. subdural haematoma. Subacute encephalopathy develops over days or weeks, and the differential additionally includes intracranial tumours or infections, and systemic inflammatory disorders, including cerebral vasculitis.
Encephalitis is encephalopathy with one or more of: fever, focal neurological findings, cerebrospinal fluid (CSF) pleocytosis, or electroencephalogram (EEG) or neuroimaging findings consistent with encephalitis. It may be infectious, non-infectious or of unknown aetiology2.
Limbic encephalitis (LE) is an uncommon condition and is often associated with underlying malignancies, commonly lung, breast and testicular cancer. The condition is thought to be autoimmune in origin. It is often possible to detect antibodies against neuronal antigens and the nature of the antibodies indicates likely aetiology and response to therapy. If the detected antibodies are amongst those known to be associated with other paraneoplastic syndromes then the response to immunosuppression is poor. However the detection of antibodies to cell surface antigens such as voltage-gated potassium channels (VGKCs) suggests a lesser risk for an underlying cancer and better response to immunosuppression.
The diagnosis of limbic encephalitis is complex. There is a large degree of variability in presentation but typical features include confusion, seizures, short-term memory loss or psychiatric symptoms. These symptoms should be in association with one or more of the following: (1) neuroimaging (MRI or positron emission tomography) evidence of temporal lobe involvement; (2) CSF inflammatory abnormalities (pleocytosis, increased protein concentration or oligoclonal bands); or (3) detection of antibodies that occur in association with limbic encephalitis. Investigations should exclude systemic autoimmune inflammatory conditions and to establish that the LE is not paraneoplastic, authorities recommend whole-body CT or FDG-PET scanning.
Status Epilepticus (SE)
A condition in which epileptic activity persists for 30 minutes or more. The seizures can take the form of prolonged seizures or repetitive attacks without recovery in between. Most episodes of status develop without a prior history of epilepsy, and these are almost always caused by acute cerebral disturbances; common causes are cerebral infection, trauma, cerebrovascular disease, cerebral tumour, acute toxic or metabolic disturbances. In patients with pre-existing epilepsy, status can be precipitated by drug withdrawal, intercurrent illness or metabolic disturbance, or the progression of the underlying disease.
Refractory status epilepticus
Persistent seizure activity despite therapy with benzodiazepines and phenytoin or fosphenytoin has been suggested as a definition of refractory SE. Refractory SE develops in 31% to 43% of patients with SE, with a mortality rate of at least 16% to 22%. The commonest cause of refractory SE is encephalitis, followed by cerebrovascular disease, alcohol toxicity, hypoxic brain injury and multiple sclerosis. The presence or development of hyponatraemia early in the course of status epilepticus may facilitate the development of refractoriness.
Non convulsive status epilepticus
Nonconvulsive status epilepticus (NCSE) is persistent abnormal electrical activity in the brain without convulsions and constitutes approximately 20-25% of all cases of SE. These seizures would usually manifest as periods of impaired consciousness or cognition. In ventilated patients the diagnosis is not apparent without EEG monitoring. EEG monitoring for seizure activity is a useful adjunct when treating status epilepticus in the critical care environment and is commonly used when overt seizures have been observed in comatose patients. However, NCSE can present in comatose patients with no overt signs of seizure activity. In a prospective study in America, EEGs were performed on 236 comatose patients, without clinically overt seizure activity, in an ICU and 19 patients (8%) were found to be in NCSE. This under-diagnosis is likely to be common and results in suboptimal management and outcome.
In addition to utility for diagnosis, EEG monitoring may also be used to guide therapy. However, there is no consensus on what aspect of the EEG should be targeted. There is no evidence that targeting burst suppression on the EEG improves outcome and indeed, sustained EEG burst suppression is elusive and temporary achievement of burst suppression does not improve prognosis2.
Reaching the ultimate diagnosis was difficult and potentially the delay in diagnosis resulted in delay of effective therapy. Although there is a clear rationale for immunosuppression in limbic encephalitis, robust evidence of efficacy is currently lacking.
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- Bataller L, Kleopa KA, Wu GF et al. Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. J. Neurol. Neurosurg. Psychiatry, 2007;78(4):381-385
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