The Dedicated Student
The Tale
We begin our story with a dedicated and hard-working Indonesian student in her early 20s studying medical sciences at the prestigious University of Melbourne. This was no ordinary international student; despite still being in the middle of her undergraduate degree, she had also recently commenced an internship at the Baker Institute, an internationally renowned medical research facility. Our student was forced to work hard and was determined to be successful. Unfortunately, one inadvertent yet unavoidable consequence of such ambition is stress (a challenge that goes beyond the coping abilities of an individual); our student certainly felt the combined assault of study and work, yet she chose not to relay this feeling to her family in Indonesia. She called her mother in Indonesia often, who never forgot to mention how proud they all were of the achievements of her daughter - so she could not let her family down by telling them the truth; that the stress levels were so high she was just barely getting by.
Thus, our student pushed on.
After several months of this, during one of their routine phone calls, the mother noted that her daughter sounded different over the phone. Our student stated that she "had a problem" and finally admitted to feeling stressed for many months. Moreover, our student told her mother that she felt "guilty" over the realization that she may not be able to continue on with the internship at the Baker Institute. After some consoling from her mother, the conversation ended, and no more was said. That was not the end of her ordeal, however, but merely the beginning.
Over the subsequent week, our student started acting strangely. Normally a quiet and introverted person, her friends at university noticed that she was becoming more and more outspoken, repeatedly stating that she "did not know what reality was". More alarming statements appeared as time went on. Our student began to repeatedly say that she "just wanted to end it all" and the she could "just commit suicide". By the end of the week, she had nonsensical speech, and she was brought to our hospital emergency department by her concerned friends.
She was attended to by our busy emergency doctors, who made several observations. First, our student could or would not answer simple questions. She seemed to pay no attention to anything asked of her. In addition, she monotonously chanted the following phrases over and over:
"I am here to confess my sins."
"I need to reset my life".
"I am lying to my Mum".
Requesting a piece of paper, she then proceeded to write down a single word in capital letters over and over:
KEMATIAN
KEMATIAN
KEMATIAN
In Indonesian, "kematian" means "death". A bit concerning, to say the least.
A brief history was obtained. The sequence of events up to this point was noted, and the friends of our student also mentioned that she had not been sleeping well for many months. There was otherwise not much to go on. No, she had no medical or psychiatric history. No, she did not smoke, drink alcohol, or use illicit drugs. No, there was no known family history of psychiatric illness. No, she took no medications other than the oral contraceptive pill and had no allergies.
On examination, our student was neatly dressed. Her blood pressure and heart rate were normal and her heart and lungs sounded fine. Besides the obvious change in mental state, the neurological examination was also normal. Her tone, power, reflexes, and sensation were normal, and she could walk and hold her balance without difficulty.
A few blood tests and a scan were ordered. The blood tests included tests for thyroid function, an important test to do as thyrotoxicosis (a condition in which excessive levels of thyroid hormone accumulate within the blood; this can happen for a variety of reasons, including thyroid overactivity from immune dysfunction, a tumour or inflammation of the thyroid gland, medications, and excess iodine in the diet, notably from kelp) can result in psychosis. However, the thyroid levels came back normal. A computed tomography (CT) scan (a three dimensional x-ray) of the head was likewise normal.
Our unfortunate student was diagnosed with first episode of psychosis (a nonspecific term meaning that somebody has lost contact with reality, which has never happened to them before). She was admitted under psychiatry and commenced on sedating medications.
Her admission under psychiatry lasted for five days. During this time, our student deteriorated. Sometimes she was agitated, displaying excessive amounts of excitement and restlessness. At other times, she was catatonic and would lie still with her eyes open for up to an hour at a time, not reacting to anyone or anything - just staring straight ahead, immobile. The psychiatrists tried to compensate with antipsychotic medication, and even attempted electroconvulsive therapy (ECT) to break the psychosis. ECT is a standard psychiatric treatment in which seizures are induced to treat depression, schizophrenia, mania, and catatonia. It is often depicted in film and television as painful, but in western countries it is administered with anesthesia and muscle relaxants. The mechanism remains elusive and the effectiveness of the procedure is contentious, but it does seem to help some patients.
At any rate, ECT did nothing to help our student. The day after her ECT session, she developed a high-grade fever. She was flushed and sweating profusely. The psychiatrists had emptied their bag of tricks and requested a consultation from the general physicians. The general physicians assessed her and concluded that our student might have meningoencephalitis (a condition that resembles meningitis, an infection or inflammation of the membranes that surround the brain, as well as encephalitis, an infection or inflammation of the brain itself). Taking over the care of our student, the general physicians performed blood cultures (this involves attempting to grow any bacteria that may be multiplying within the blood of a patient so as to identify them, which can direct therapy towards the best antibiotics) and a lumbar puncture (inserting a needle into the lower back to obtain cerebrospinal fluid, safe and painless if done properly). The general physicians also started three different intravenous antibiotics simultaneously, and ordered an electroencephalogram (EEG).
An EEG is a device that records the spontaneous electrical activity of the brain along the scalp. Specifically, it measures voltage fluctuations created by currents flowing within the brain, probably along circuits between the thalamus and the cerebral cortex. It is performed by sticking electrodes all over the scalp and recording voltage changes from each electrode. The EEG shows voltage fluctuations as waves on a tracing. In a normal person, the wave frequencies are indicative of the degree of wakefulness of that person - in relaxed wakefulness, alpha waves (waves with a frequency of 8 to 13 Hz) usually predominate; in states of attention and intense concentration, gamma waves (usually 30 to 50 Hz) predominate; in states of drowsiness, theta waves (4 to 8 Hz) predominate; and in deep sleep, delta and theta waves (1 to 8 Hz) predominate.
Thus, our student pushed on.
After several months of this, during one of their routine phone calls, the mother noted that her daughter sounded different over the phone. Our student stated that she "had a problem" and finally admitted to feeling stressed for many months. Moreover, our student told her mother that she felt "guilty" over the realization that she may not be able to continue on with the internship at the Baker Institute. After some consoling from her mother, the conversation ended, and no more was said. That was not the end of her ordeal, however, but merely the beginning.
Over the subsequent week, our student started acting strangely. Normally a quiet and introverted person, her friends at university noticed that she was becoming more and more outspoken, repeatedly stating that she "did not know what reality was". More alarming statements appeared as time went on. Our student began to repeatedly say that she "just wanted to end it all" and the she could "just commit suicide". By the end of the week, she had nonsensical speech, and she was brought to our hospital emergency department by her concerned friends.
She was attended to by our busy emergency doctors, who made several observations. First, our student could or would not answer simple questions. She seemed to pay no attention to anything asked of her. In addition, she monotonously chanted the following phrases over and over:
"I am here to confess my sins."
"I need to reset my life".
"I am lying to my Mum".
Requesting a piece of paper, she then proceeded to write down a single word in capital letters over and over:
KEMATIAN
KEMATIAN
KEMATIAN
In Indonesian, "kematian" means "death". A bit concerning, to say the least.
A brief history was obtained. The sequence of events up to this point was noted, and the friends of our student also mentioned that she had not been sleeping well for many months. There was otherwise not much to go on. No, she had no medical or psychiatric history. No, she did not smoke, drink alcohol, or use illicit drugs. No, there was no known family history of psychiatric illness. No, she took no medications other than the oral contraceptive pill and had no allergies.
On examination, our student was neatly dressed. Her blood pressure and heart rate were normal and her heart and lungs sounded fine. Besides the obvious change in mental state, the neurological examination was also normal. Her tone, power, reflexes, and sensation were normal, and she could walk and hold her balance without difficulty.
A few blood tests and a scan were ordered. The blood tests included tests for thyroid function, an important test to do as thyrotoxicosis (a condition in which excessive levels of thyroid hormone accumulate within the blood; this can happen for a variety of reasons, including thyroid overactivity from immune dysfunction, a tumour or inflammation of the thyroid gland, medications, and excess iodine in the diet, notably from kelp) can result in psychosis. However, the thyroid levels came back normal. A computed tomography (CT) scan (a three dimensional x-ray) of the head was likewise normal.
Our unfortunate student was diagnosed with first episode of psychosis (a nonspecific term meaning that somebody has lost contact with reality, which has never happened to them before). She was admitted under psychiatry and commenced on sedating medications.
Her admission under psychiatry lasted for five days. During this time, our student deteriorated. Sometimes she was agitated, displaying excessive amounts of excitement and restlessness. At other times, she was catatonic and would lie still with her eyes open for up to an hour at a time, not reacting to anyone or anything - just staring straight ahead, immobile. The psychiatrists tried to compensate with antipsychotic medication, and even attempted electroconvulsive therapy (ECT) to break the psychosis. ECT is a standard psychiatric treatment in which seizures are induced to treat depression, schizophrenia, mania, and catatonia. It is often depicted in film and television as painful, but in western countries it is administered with anesthesia and muscle relaxants. The mechanism remains elusive and the effectiveness of the procedure is contentious, but it does seem to help some patients.
At any rate, ECT did nothing to help our student. The day after her ECT session, she developed a high-grade fever. She was flushed and sweating profusely. The psychiatrists had emptied their bag of tricks and requested a consultation from the general physicians. The general physicians assessed her and concluded that our student might have meningoencephalitis (a condition that resembles meningitis, an infection or inflammation of the membranes that surround the brain, as well as encephalitis, an infection or inflammation of the brain itself). Taking over the care of our student, the general physicians performed blood cultures (this involves attempting to grow any bacteria that may be multiplying within the blood of a patient so as to identify them, which can direct therapy towards the best antibiotics) and a lumbar puncture (inserting a needle into the lower back to obtain cerebrospinal fluid, safe and painless if done properly). The general physicians also started three different intravenous antibiotics simultaneously, and ordered an electroencephalogram (EEG).
An EEG is a device that records the spontaneous electrical activity of the brain along the scalp. Specifically, it measures voltage fluctuations created by currents flowing within the brain, probably along circuits between the thalamus and the cerebral cortex. It is performed by sticking electrodes all over the scalp and recording voltage changes from each electrode. The EEG shows voltage fluctuations as waves on a tracing. In a normal person, the wave frequencies are indicative of the degree of wakefulness of that person - in relaxed wakefulness, alpha waves (waves with a frequency of 8 to 13 Hz) usually predominate; in states of attention and intense concentration, gamma waves (usually 30 to 50 Hz) predominate; in states of drowsiness, theta waves (4 to 8 Hz) predominate; and in deep sleep, delta and theta waves (1 to 8 Hz) predominate.
Let's walk through this EEG. The eight top lines represent voltage changes between electrodes on the right side of the brain, the two middle lines represent voltage changes from the midline of the brain, the eight lines below them represent voltage changes from the left side of the brain, and the three bottom lines can be ignored. All of the waves have a frequency of 3 Hz, which puts them in the delta range. This EEG is consistent with a severe encephalopathy (a nonspecific term meaning "brain disorder").
|
Although the EEG was consistent with a severe encephalopathy, one of the alternative possibilities considered at the time was that it might also represent repeated episodes of non-convulsive status epilepticus (status epilepticus refers to any seizure that persists for longer than five minutes; it is usually associated with convulsions, but not always) and so our unfortunate student was loaded with anti-epileptic medications. She was now on a host of drugs, including antipsychotics, antibiotics, and anti-epileptics. None of this made any difference.
At this point, the general physicians requested a neurology consult. With the concern over status epilepticus, we took our student over immediately. Being on ward service, I went over to see our new arrival. Brief inspection showed that our student was a slender young lady of Indonesian ancestry. She was completely confused and her speech completely nonsensical. She continued to alternate between agitation and catatonia every thirty minutes or so. She was also drooling copious amounts of saliva from her mouth, still had her fever, was hypertensive (high blood pressure) at 150/90, and her heart rate was tachycardic (fast) at 150 beats per minute (the normal range is 60 to 100 beats per minute). On examination, our student had greatly increased tone (stiffness) in all four of her limbs. Her power, tendon reflexes, and plantar reflex (also known as the Babinski response, elicited by rubbing the bottom of the foot in a particular way with a blunt instrument) were all normal.
I had a sneaking suspicion that here was a condition that I had read about, but never before encountered - a type of autoimmune encephalitis in which antibodies from one's own immune system target the N-methyl-D-aspartate (NMDA) receptor found on many neurons in the brain, resulting in brain inflammation (redness and swelling). However, I had to think out of the box so as not to miss any other possibilities, which included neuroleptic malignant syndrome (a serious disorder resulting from an adverse reaction to antipsychotic drugs - which our student had been given plenty of - that presents with muscle rigidity, fever, and unstable autonomic functions such as blood pressure and heart rate) as well as a viral encephalitis (inflammation of the brain from any number of different viruses - of all of the viruses out there I was worried mostly about herpes simplex virus encephalitis - resulting in confusion, fever, headache, and occasionally seizures). All of these conditions needed to be checked.
Time was running out, and our student needed a diagnosis. My resident and I ordered a few tests to help us narrow down our list of differentials. To assess for autoimmune encephalitis against the NMDA receptor, we called our hospital lab and asked them to test for the presence of anti-NMDA receptor antibodies in the cerebrospinal fluid from the lumbar puncture done earlier (the lab always keeps any sample they receive for at least a few days). To assess for herpes simplex virus encephalitis, we also asked the lab to test for the presence of herpes simplex virus DNA in the cerebrospinal fluid. To assess for neuroleptic malignant syndrome, we ordered a blood test to check the level of creatine kinase (an enzyme almost entirely expressed by muscle tissue that can be greatly elevated in neuroleptic malignant syndrome). Over the next few days, the anti-NMDA receptor antibody came back strongly positive, the herpes simplex virus test was negative, and the creatine kinase was high - but not ferociously high - at 500 IU/L.
At long last, we had a diagnosis - our dedicated student had anti-NMDA receptor encephalitis, probably triggered by physical and emotional stress.
At this point, the general physicians requested a neurology consult. With the concern over status epilepticus, we took our student over immediately. Being on ward service, I went over to see our new arrival. Brief inspection showed that our student was a slender young lady of Indonesian ancestry. She was completely confused and her speech completely nonsensical. She continued to alternate between agitation and catatonia every thirty minutes or so. She was also drooling copious amounts of saliva from her mouth, still had her fever, was hypertensive (high blood pressure) at 150/90, and her heart rate was tachycardic (fast) at 150 beats per minute (the normal range is 60 to 100 beats per minute). On examination, our student had greatly increased tone (stiffness) in all four of her limbs. Her power, tendon reflexes, and plantar reflex (also known as the Babinski response, elicited by rubbing the bottom of the foot in a particular way with a blunt instrument) were all normal.
I had a sneaking suspicion that here was a condition that I had read about, but never before encountered - a type of autoimmune encephalitis in which antibodies from one's own immune system target the N-methyl-D-aspartate (NMDA) receptor found on many neurons in the brain, resulting in brain inflammation (redness and swelling). However, I had to think out of the box so as not to miss any other possibilities, which included neuroleptic malignant syndrome (a serious disorder resulting from an adverse reaction to antipsychotic drugs - which our student had been given plenty of - that presents with muscle rigidity, fever, and unstable autonomic functions such as blood pressure and heart rate) as well as a viral encephalitis (inflammation of the brain from any number of different viruses - of all of the viruses out there I was worried mostly about herpes simplex virus encephalitis - resulting in confusion, fever, headache, and occasionally seizures). All of these conditions needed to be checked.
Time was running out, and our student needed a diagnosis. My resident and I ordered a few tests to help us narrow down our list of differentials. To assess for autoimmune encephalitis against the NMDA receptor, we called our hospital lab and asked them to test for the presence of anti-NMDA receptor antibodies in the cerebrospinal fluid from the lumbar puncture done earlier (the lab always keeps any sample they receive for at least a few days). To assess for herpes simplex virus encephalitis, we also asked the lab to test for the presence of herpes simplex virus DNA in the cerebrospinal fluid. To assess for neuroleptic malignant syndrome, we ordered a blood test to check the level of creatine kinase (an enzyme almost entirely expressed by muscle tissue that can be greatly elevated in neuroleptic malignant syndrome). Over the next few days, the anti-NMDA receptor antibody came back strongly positive, the herpes simplex virus test was negative, and the creatine kinase was high - but not ferociously high - at 500 IU/L.
At long last, we had a diagnosis - our dedicated student had anti-NMDA receptor encephalitis, probably triggered by physical and emotional stress.
The Condition
Anti-NMDA receptor encephalitis results from B cell targeting of the NMDA receptors of neurons within the brain. In most cases, patients with this condition have a teratoma (a strange kind of tumour that contains tissue or organ components resembling normal tissue, such as brain or liver tissue). The immune system B cells identify the teratoma as pathological and produce antibodies against it, but if the teratoma expresses the NMDA receptor, the neurons displaying NMDA receptors in the brain may lamentably and inadvertently be targeted for destruction as well. Anti-NMDA receptor encephalitis usually affects young women of African or Asian origin in their twenties or thirties, and over half of these patients have a detectable ovarian teratoma (Titulaer et al, 2013).
Anti-NMDA receptor encephalitis displays a progression of symptoms (Gable et al, 2009), many of which our student displayed (shown in bold), in the following order: (1) A viral-like prodrome (headache, fever). (2) Psychiatric disturbances (hallucinations, suicidal ideation). (3) Anterograde amnesia (memory loss after the illness starts). (4) Involuntary movements (dyskinesias, seizures). (5) Loss of responsiveness (such as states of catatonia). (6) Hypoventilation (inadequate breathing). (7) Autonomic instability (variations in blood pressure and salivation). Treatment consists of intravenous methylprednisolone (a powerful steroid that reduces inflammation) plus intravenous immunoglobulin (made from the pooled antibodies of blood donors, this somehow reduces the levels of harmful antibodies) or plasmapheresis (blood plasma is removed from the patient, treated to dispose of the antibodies, and then returned) for several days (Dalmau et al, 2011). Any detected teratomas must be surgically removed. If the patient does not improve sufficiently from these measures, chronic immunosuppressing medications such as rituximab (a monoclonal antibody that destroys B cells) or cyclophosphamide (a nitrogen mustard alkylating agent that interferes with DNA replication) can be tried. According to the largest and most recent review to date, 79% of treated patients will recover completely, 15% will be left with a mild to severe deficit, and 6% will die (Titulaer et al, 2013). Without treatment, these odds are worse. |
The immune system B cell makes antibodies against teratoma antigens, but if that teratoma happens to express the NMDA receptor, the brain gets targeted too.
Plasma B cells produce Y-shaped proteins called antibodies or immunoglobulins. They normally neutralize invaders such as bacteria and viruses.
Diagram of a synapse (junction between two neurons). The vesicles of the first neuron release neurotransmitters into the synaptic cleft which then bind to neurotransmitter receptors on the second neuron. On many neurons the receptors are NMDA receptors, targeted by the body's own B cells and antibodies.
|
Epilogue
As soon as we suspected anti-NMDA receptor encephalitis in our student, we commenced treatment with five days of intravenous methylprednisolone and intravenous immunoglobulin while we waited for the result of the anti-NMDA receptor antibody test to come back from the lab (we also kept up some intravenous acyclovir - an antiviral medication - while we waited for the herpes simplex virus result too, just in case, but we slowly weaned off the anti-epileptic medications as we were never convinced that she had ever had non-convulsive status epilepticus). Within a few day, our student improved; specifically, the episodes of agitation and catatonia disappeared, the fever vanished, and the blood pressure and heart rate normalized. She remained extremely confused though. We arranged an ultrasound of her ovaries and found only a simple cyst (fluid-filled sac), which is a far cry from a teratoma, but we asked our excellent surgeons to remove it anyways. We monitored her for another week after the courses of methylprednisolone and intravenous immunoglobulin had been completed, and although she had improved, a moderate degree of confusion remained. Going partly with the recommendations from the literature, we commenced weekly rituximab. When the confusion had settled to a manageable point about two months later, we discharged our student to a rehabilitation facility. I continued to communicate with the facility by phone over the next few months, but after a while I heard that our student was nearly back to normal and would be discharged soon. I never heard about her again.
Half a year later, I was walking beside the cafeteria of our hospital when I noticed a young lady walking towards me. She looked familiar, but I could not place her until she had walked past me (people look so different when they are extremely ill). Yes, it was our dedicated student - looking back to normal. She did not recognize me, for though we had seen each other almost every day during her two month stay in hospital, the anterograde amnesia she experienced as part of her condition ensured that she had not remembered any of the people involved in her treatment during the time of illness.
I smiled, and walked on.
Half a year later, I was walking beside the cafeteria of our hospital when I noticed a young lady walking towards me. She looked familiar, but I could not place her until she had walked past me (people look so different when they are extremely ill). Yes, it was our dedicated student - looking back to normal. She did not recognize me, for though we had seen each other almost every day during her two month stay in hospital, the anterograde amnesia she experienced as part of her condition ensured that she had not remembered any of the people involved in her treatment during the time of illness.
I smiled, and walked on.
References
Dalmau et al. 2011. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology 10(1), 63-74.
Gable et al. 2009. Anti-NMDA receptor encephalitis: Report of ten cases and comparison with viral encephalitis. European Journal of Clinical Microbiology and Infectious Diseases 28(12), 1421-1429.
Titulaer et al. 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet Neurology 12(2), 157-165.
Dalmau et al. 2011. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology 10(1), 63-74.
Gable et al. 2009. Anti-NMDA receptor encephalitis: Report of ten cases and comparison with viral encephalitis. European Journal of Clinical Microbiology and Infectious Diseases 28(12), 1421-1429.
Titulaer et al. 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet Neurology 12(2), 157-165.