Anti Nmda Receptor Encephalitis Biology Essay

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Anti-N-methyl-D-aspartate receptor encephalitis is a recently described neurological disorder and an increasingly recognized cause of psychosis, movement disorders and autonomic dysfunction. As discovery of tumour and its removal is the focus of initial treatment in this group of patients, anaesthetists will encounter more such cases in the near future. We report a patient with anti NMDA receptor encephalitis who underwent laparotomy and cystectomy under bilateral transversus abdominis plane (TAP) block. We also discuss the anaesthetic issues associated with anti-NMDA receptor encephalitis.

Introduction

Anti-NMDA receptor encephalitis was first described by J Dalmau and colleagues in 2007. (1) In recent years more than 400 cases have since been diagnosed. However literature regarding the anaesthetic management in patients with anti-NMDA receptor encephalitis is scarce, with only 3 case reports in recent years to guide anaesthetic management. (2-4) This is somewhat surprising - firstly, because a large number of patients with anti-NMDA receptor encephalitis will need surgery for removal of tumour or other incident surgery, and secondly because many anaesthetic drugs act upon the NMDA receptor and pathology here is likely to affect the actions of anaesthetic drugs as well. We describe here a patient with anti-NMDA receptor encephalitis who was given a bilateral transversus abdominis plane block as the sole anaesthetic for removal of ovarian tumour, the first such case report.

Case Report

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A previously well 20-year-old presented to a private hospital with sudden onset of generalized tonic-clonic seizures which was preceded by a two-day history of running nose. Further enquiry revealed recent memory loss, visual hallucinations and abnormal behavior such as restlessness and talking to herself. She was afebrile, haemodynamically stable and neurological findings were normal. Her white cell count, MRI brain and lumbar puncture were normal and electroencephalogram showed slow background activity. She was treated as a case of aseptic meningitis with intravenous acyclovir and started on antiepileptics. However, her condition did not improve after one week and thus she was referred to our institution for further management.

In our institution, she was started on a course of intravenous methylprednisolone for five days while being continued on intravenous acyclovir, lamotrigine and risperidone. She continued to show behavioural abnormalities and had one episode of seizures. A diagnosis of anti NMDA receptor encephalitis was suspected. Her serum was tested by indirect immunofluorescent antibody test (Luebeck, Germany) and was positive for antibodies against the NMDA receptor (Specificity 100%), therefore confirming the diagnosis. An abdominal CT scan revealed a left adnexal mass 4x4x4cm in size, likely to be an ovarian teratoma.

This patient was then scheduled for elective laparotomy and cystectomy. Preoperatively a joint discussion was held with the patient's parents regarding the mode of anaesthesia and the risks of operation. Regional anaesthesia with a bilateral transversus abdominis plane block was planned.

During pre-operative assessment, she refused to open eyes, was unable to follow commands and occasionally showed abnormal behaviours such as inappropriate laughing and jerking movements. Baseline blood pressure was 140/95mmHg, heart rate 115 beats per minute (bpm) and oxygen saturations were 98% on oxygen 3L/min.

In the operating theatre, with standard monitoring, ultrasound-guided (Sonosite M-turbo®, Sonosite Inc., Bothell, WA, USA) bilateral transversus abdominis plane block was done under aseptic technique. A linear probe 13-6 MHz was placed at the lateral abdominal wall in the midaxillary line, between the subcostal margin and iliac crest. A 21G, 80mm insulated needle (Stimuplex® A, B.Braun, Melsungen AG, Melsungen, Germany) was directed to the transversus abdominis plane between the internal oblique and transversus abdominis muscles using the in-plane technique. 20mls of levo-bupivacaine 0.25% was injected into the transversus abdominis fascial plane on each side.

After 15 minutes, the adequacy of block was assessed by response to pin prick. As the patient was unable to follow commands, we relied on her facial expressions, movement and sympathetic responses such as heart rate. Surgery was allowed to start when we were satisfied that there was no response to pin prick up to T8 dermatomal level.

A Pfennensteil incision was made without any discomfort. During retraction and excision of the tumour, 25mcgs of intravenous fentanyl was administered as supplementation for visceral pain. Intra-operatively, her blood pressure ranged from 110/75 to 140/95 mmHg and heart rate was 100-115bpm. Her respiratory status was stable at 18-20 breaths per minute and oxygen saturations were 99-100%. A left ovarian cystic mass measuring 4cm x 5cm was removed and the operation was completed uneventfully in 40 minutes with minimal blood loss. No episodes of hypoventilation or autonomic instability were seen.

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She remained stable post-operatively with BP of 135/80 - 145/95 mmHg and HR of 105-115bpm in recovery. She was calm but refused to open eyes to call or pain. After an hour she was discharged to the acute cubicle in the neurology ward. SC morphine 5mg QID, Tab Paracetamol 1g QID and Tab Celecoxib 200mg OD were prescribed as post-operative analgesia.

On day 7 post-operation, she had more eye opening episodes but still remained mostly unresponsive. Her haemodynamic and respiratory status remained stable. In view of little improvement in symptoms, plasma exchange was started on day 14 post-operation and 5 cycles were completed. Histopathology examination of the excised tumour confirmed the diagnosis of mature cystic teratoma.

One week after completion of plasma exchange, she showed marked clinical improvement. She was alert, talking coherently and fit free. Throughout her stay, she did not show any episodes of autonomic instability or hypoventilation. Although she complained of occasional visual hallucinations, she had an excellent functional recovery and was discharged home after one month of hospital admission. Upon questioning, she had no recollection of incidents during her hospital stay and specifically could not recall anything about the operation.

DISCUSSION

The NMDA receptor

NMDA receptors are ionotropic glutamate receptors, comprised of different subunits. Eight different NR1 subunits, four NR2 subunits (A, B, C and D) and two NR3 subunits (A and B) have been identified. The NMDA receptor most likely consists of four subunits (tetrameric) with at least one NR1 and one NR2 subtype. (5)

The receptor controls a cation channel that is highly permeable to monovalent ions and calcium. At resting membrane potential the NMDA receptor channels are blocked by extracellular Mg.(6) Simultaneous binding of glutamate to NR2 and glycine, the coagonist, to NR1 is required for receptor activation.

Anti- NMDA receptor encephalitis

This was first described in 2007 by J Dalmau and colleagues, (1) who reported a case series of 100 patients, mainly young women (median age 23 years, 91% women) who had antibodies against NR-1 NR-2 heteromers. All presented with psychiatric symptoms, and 59% had tumours, most commonly ovarian teratoma. Since then anti- NMDAR encephalitis is being increasingly recognised.

The clinical features include a prodromal phase of headache, fever, nausea or upper respiratory tract symptoms. This is followed within 2 weeks by the psychotic phase, in which patients present with anxiety, insomnia, delusions, mood dysregulation and severe behavioural or personality disturbances. (7, 8)This psychotic phase then progresses to an 'unresponsive' state, in which periods of agitation and catatonia can alternate. Of interest to the anaesthetist are the findings of autonomic instability at this stage, which include hyperthermia, tachycardia, hypertension and bradycardia. In their first series of 100 patients, Dalmau and colleagues reported that 7 patients had prolonged cardiac pauses and 4 needed pacemakers. (1)In addition there are frequently abnormal movements, increased muscle tone and dyskinesias which may include clenching of the teeth or jaw dystonia. Another significant symptom at this 'unresponsive' stage is the possibility of hypoventilation of central origin. (7, 8) Many patients require ventilation in the intensive care unit.

Treatment for the disorder consists of immunotherapy and removal of tumour. Immunotherapy includes corticosteroids, intravenous immunoglobulins, plasma exchange or second line drugs such as rituximab and cyclophosphamide. Patients should be screened for an underlying tumour, most commonly an ovarian teratoma. Removal of tumour has been reported to result in substantial improvement in 80% of patients. (8) Overall, about 75% of patients with anti NMDAR encephalitis recover or have mild sequelae, whereas others remain severely disabled or die. The estimated mortality is 4%. (8)

Anaesthetic Considerations

Drugs acting at the NMDA receptor

Many anaesthetic drugs act at the NMDA receptor. NMDA antagonists include ketamine, phencyclidine, dextromethorphan, nitrous oxide and xenon. Tramadol and methadone act both at opioid and NMDA receptors. These drugs should be avoided as there is likely to be increased sensitivity and possibly a worsening of symptoms.

Other anaesthetic agents may act indirectly at the NMDA receptor, including volatile anaesthetics. Halogenated anaesthetics reduce NMDA- activated currents, although their effects on GABAA receptors may be dominant. (9-11) Therefore the effect of volatile agents may be unpredictable. Three previous case reports used desflurane (3), isoflurane (3) and sevoflurane (2, 4), and none reported increased sensitivity to the volatile anaesthetics.

Although propofol is postulated to act via the GABAA receptor and sodium channel, one 14 year old patient was reported to have unexpected profound hypotension following propofol induction at a dose of 3mg/kg. (4) This highlights the fact that NMDA receptors play an important role in the mechanism of action of many anaesthetic drugs.

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Effects of the disease

Anaesthetists should consider inserting invasive blood pressure monitoring and temperature monitoring as many patients show autonomic instability. Increased temperature may mimic malignant hyperthermia.

An important issue of concern would be central hypoventilation as a result of the disease. This may lead to difficulty weaning the patient from the ventilator, or to unexpected need for reintubation. It would be prudent to closely monitor patients in a high dependency setting following general anaesthesia. Prolonged ventilation may necessitate a tracheostomy, such as in previous case reports. (3)

Abnormal movements and dyskinesias may give rise to difficulty with patient positioning, nerve injuries and difficult intravenous access due to rigidity, dystonia or opisthotonus. Jaw clenching or broken teeth may lead to difficulties during intubation.

In the catatonic or psychotic state patients will be unable to cooperate and informed consent will have to be taken from the nearest relatives.

Is General Anaesthesia then the Anaesthetic of Choice?

Patients with anti-NMDA receptor encephalitis are likely to already have a reduced perception of pain. (12) Pain associated with nerve or peripheral tissue injury involves NMDA receptor activation, especially the NR2B subunit. (6, 13) NMDA receptor antagonists are potent analgesics, such as ketamine which acts by blocking the open channel, and reducing the frequency of channel opening. Peripheral NMDA receptor antagonism may even be effective in preventing visceral pain. (14) In anti NMDA receptor encephalitis, the main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. (1) The pathogenic mechanism is said to be antibody mediated capping and internalisation of NMDA receptors, leading to reduced NMDA receptor density and NMDAR mediated currents. (8, 10) This may be why patients mimic the features of dissociative anaesthesia produced by ketamine.

In addition, patients are unlikely to recall intraoperative events even without general anaesthesia. Persisting amnesia of the entire process is a characteristic feature of anti-NMDA receptor encephalitis, possibly due to disruption of synaptic plasticity. (1)

We therefore felt that a transversus abdominis plane block would be sufficient as the sole anaesthetic in this patient, and would allow us to avoid both the risks associated with general anaesthesia (unpredictable effects of anaesthetic drugs, autonomic instability, central hypoventilation leading to prolonged artificial ventilation, tracheostomy and its attendant risks such as ventilator associated pneumonias) as well as the risks of central neuraxial block (recent encephalitis, possible increased intracranial pressure, uncooperative patient). Several factors contributed to its success. The tumour was relatively small, and the experienced surgeon was able to assure a small incision and a quick surgery of 40 minutes with minimal handling of the abdominal viscera.

Transversus abdominis plane block

This is an abdominal field block, with local anaesthetic deposited in between the internal oblique and transversus abdominis muscles to block the anterior rami of spinal nerves T7 to L1 traversing in this plane. It blocks somatic sensation to the abdominal skin, muscles and parietal peritoneum but not visceral sensation.(15)Therefore it is usually used to provide analgesia for lower abdominal surgery, and very rarely as the sole anaesthetic.

Conclusion

We present a case of a patient with anti-NMDA receptor encephalitis who underwent laparotomy and cystectomy with a bilateral transversus abdominis plane block as the sole anaesthetic. The anaesthetic considerations in patients with this recently discovered encephalitis are highlighted. We postulate that an altered perception to pain may contribute to the feasibility of bilateral TAP block as the sole anaesthetic for lower abdominal surgery in this group of patients and avoid the risks associated with a general anaesthetic.