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Lapkas Atin3
AUTOIMMUNE ENCHEPALITIS
INTRODUCTION
Until recently, autoimmune encephalitis was restricted to the syndrome
described as paraneoplastic limbic encephalitis (LE), an infrequent paraneoplastic
neurological syndrome (PNS) mainly associated with lung cancer 1. Paraneoplastic
LE used to run a severe clinical course that rarely improved despite removal of the
tumour and intensive treatment with immunotherapy. However, in the last five years,
the characterization of different antibodies against neuronal surface antigens has led
to the identification of different types of LE and other encephalitic syndromes. These
are important to recognize because they usually improve with immunotherapy and
some of them are associated with tumours that can be diagnosed at an early stage
when the chances of cure are highest. Taken together, these encephalitides are not as
unusual as previously believed. In a retrospective analysis of encephalitis of unknown
origin admitted to an intensive care unit, 1% were finally identified as autoimmune.1
EPIDEMIOLOGY
The overall incidence of the condition is unknown. 2 More recent figures
produced by the California Encephalitis Project showed that the disease had a higher
incidence than its individual viral counterparts in patients <30 years. 3 The largest
cases series to date characterized 577 patients with anti-NMDA receptor encephalitis.
The epidemiologic data were limited but this study provides the best approximation
of disease distribution. This case series found that women are disproportionally
affected, with 81% of cases reported as female. Disease onset is skewed towards
children, with a median age of diagnosis of 21 years. Over a third of cases were
children, while only 5% of cases were patients over the age of 45. This same review
found showed that 394 out of 501 patients (79%) had a good outcome by 24 months. 4
30 patients (6%) died and the rest were left with mild to severe deficits. This study
also confirmed that patients with the condition are more likely to be of Asian or
African origin.
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PATHOPHYSIOLOGY
The association between limbic encephalitis and malignancy is well
established with the antibodies targeting intracellular neuronal structures. The anti
NMDA receptor is an extracellular target and as we have seen, nearly half of all
patients will not have a malignancy, particularly in the younger cohort of patients.
The NMDA receptor is found throughout the brain, with a far more dense
concentration in the hippocampus 5, explaining many of the clinical features seen in
the disease. Its main role is involvement in synaptic transmission and neuronal
plasticity. The receptor is made up of two subunits: NR1 which binds glycine and
NR2 which binds glutamate. For the receptor to function, both subunits must be
bound to their substrate and thus dysfunction of one leads to failure of synaptic
transmission 6. The receptor has a neuro-excitatory role and so its inhibition leads to
depression of its activity. It is hypothesised that hypo-activity of the receptor plays a
role in the pathogenesis of schizophrenia and hyperactivity linked to conditions such
as dementia and some forms of epilepsy7. In anti-NMDA receptor encephalitis,
antibodies are against the NR1 subunit of the receptor.
Hughes et al.8 cultured hippocampal neurones in cerebrospinal fluid (CSF)
containing anti NR1 receptor antibodies. This led to a decrease in the number and
density of NMDA receptor clusters. The test was then repeated with CSF of patients
at later stages of the disease and this again showed a decrease in receptor density, but
not as marked as the initial disease onset, thus showing a causal relationship between
NMDAR antibody levels and disease activity. Neuronal signals relying on anti-
NMDA receptors were reduced by anti-NR1 receptor antibodies showing that the
effects of the antibodies were reversible.
Importantly, no structural damage to the neurones was observed8. However,
when we look at neurohistochemical findings from sufferers, Tuzun et al. found
temporal lobe and hippocampal atrophy, loss of pyramidal neurones in the
hippocampus and quite extensive gliosis in the hippocampus, basal forebrain, basal
ganglia and spinal cord, consistent with areas of known receptor concentration.
Unlike other forms of limbic encephalitis, there was no lymphocytic infiltration 9.
These findings are interesting, given that in the laboratory no structural damage was
observed to the neurones, but the presence of gliosis would imply that there must be
an inflammatory aspect at some point during this process leading to scarring and thus
may well explain the prolonged or incomplete recovery that many patients go on to
have. Antibody production to the NMDA receptors are produced to a much greater
degree in cerebrospinal fluid, with levels in active disease up to 10 times higher in the
CSF compared with serum and high levels of antibody secreting cells in the CSF 10.
Low levels of complement in the CSF implies this pathway is not involved in the
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disease11 and a lack of disruption in the blood brain barrier in pathologically
examined specimens10 means it is not completely clear what the mechanism is
that starts the autoimmune process.
SYMPTOMS
Autoimmune encephalitis (AE) can produce a very wide range of neuro-psychiatric
symptoms. A major challenge in diagnosis is that different symptoms may appear at
different times and different levels of intensity, so that the disease may mimic many
other disorders. Some patients initially present with either neurological or psychiatric
symptoms, further complicating diagnosis.
3
An otherwise unexplained mixture of the above neuro-psychiatric symptoms may be
a clue that the underlying cause is autoimmune encephalitis.
At onset, the most distinctive features include prominent psychiatric
symptoms, seizures, confusion and memory loss. Patients will sometimes show
bizarre and often rather disturbing behaviours. Typically 10 to 20 days later, patients
develop a movement disorder, variations in blood pressure, heart rate and temperature
and may become less conscious. The movement disorder often consists of continuous
writhing and twitching of face and limbs but can also be a generalised slowing-down
of movement. More recently, patients with only a few of these features have been
recognized to have NMDA-receptor antibodies.
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Antigen or antibody associated with encephalitis
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substantial immunoth
recovery) erapy
Relapse if
associated
tumour not
removed
DIAGNOSIS
A quick diagnosis allows for early and aggressive treatment, improving the
opportunity for quick and full recovery.
Autoimmune encephalitis (AE) is a complex disease that often requires
collaboration among multiple medical disciplines for effective diagnosis and
treatment. Most AE patients can expect to see a team of doctors that may include
neurologists, rheumatologists, psychiatrists, immunologists and others.
AE can be caused by different antibodies. Currently there are 13 known
antibodies or triggers for AE but only one commercially available diagnostic test.
However, negative test results for anti-NMDA Antibodies and/or teratoma do not rule
out AE. A significant percentage of AE cases are caused by other, still unknown
antibodies, or by known antibodies for which a diagnostic test is not yet available.
In some AE cases an MRI test will show brain inflammation (encephalitis) and/or an
EEG test will show generalized slowing or seizure activity in the brain. These two
tests can rule out purely psychiatric causes of illness.
Too many general practitioners and even many specialists including
psychiatrists and neurologists have little if any experience diagnosing or treating AE.
If you suspect AE dont hesitate to share this information with your medical provider.
Disseminating scientific knowledge about diagnosis and treatment of the disease is
one of the primary goals of the Autoimmune Encephalitis Alliance.
Autoimmune encephalitides run a subacute clinical course and patients must
be admitted in hospital for vital support, to perform a brain MRI, whole body CT
or PET scan to look for an underlying tumour, lumbar puncture and analysis of
anti-neuronal antibodies in serum and CSF, and to start immunotherapy.
Blood tests in patients with LE and positive onconeural antibodies, there is no need to
repeat the antibody studies because the antibody levels do not correlate with the
clinical evolution. In patients with encephalitis associated with antibodies against
surface antigens the level of the antibodies tends to decrease in association with the
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clinical recovery. However, low levels may persist for years. At present, there are no
guidelines for the clinical value of repeated evaluation of antibody levels in these
encephalitides.
The symptoms and signs seen in patients with NMDA Receptor Antibody
associated Encephalitis can be distinctive and are prompting many clinicians to
request the NMDA receptor antibody test to diagnose this condition. The disease
mainly affects young people, with around 30% of cases under 18 years of age.
Women are affected more often than men.
Once a patient has been diagnosed with NMDA Receptor Antibody
Encephalitis, an underlying tumour should be looked for. While very few males have
tumours detected, recent reports suggest that between 20 and 57% of females may
have an underlying tumour. The most common tumour found in women is called an
ovarian teratoma. This is a non-cancerous tumour but it is thought to stimulate the
production of NMDA receptor antobody
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TREATMENT
Early and aggressive treatment of AE leads to the best outcomes. A number of
options are available to treat AE. These therapies are broken down into what are
considered first line and second line treatment options. One or more first line
treatments may be prescribed by your physician as soon as a patient is diagnosed with
AE. The four most common first line treatments include the following:
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removal of a teratoma (if present) that could be triggering the autoimmune
response;
use of anti-inflammatory drugs (ie. steroids);
use of plasmapheresis to remove harmful antibodies from blood; and
treatment with intravenous immunoglobulin (IVIG) which is believed to occupy
the binding sites where harmful antibodies attach to brain cells.
Early and aggressive therapy has been shown to prevent progression of the
disease.Patients who do not improve on first line treatments may be given a second
line treatment. Second line treatments are drugs that are intended to suppress the
immune system. The three most common second line drugs used for AE are:
Rituximab,
CellCept , and
Cytoxan (cyclophosphamide).
Early detection and treatment of the underlying tumour is the approach that offers
the greatest chance for neurological improvement or symptom stabilization.
Therefore, a work-up for cancer must be done in every patient with suspected
autoimmune encephalitis. In patients with LE and onconeural antibodies, where
the chances of an underlying cancer are highest, imaging studies must include a
whole body PET scan if other studies are negative. In patients with Ma2 antibodies
elective orchyectomy and serial examination of the testicle to rule out in situ
carcinomas is indicated in patients at high risk of testicular cancer such as those
with calcifications or undescended testicle(s). In women with anti-NMDA receptor
encephalitis, the ovarian teratomas are frequently small and asymptomatic. Although
oophorectomy is not recommended if the tumour screening is negative,
any small cystic and persistent lesion of the ovary must be viewed with a high
index of suspicion and its removal is recommended.12
There are no firm guidelines as to which kind of immune therapy should be
used in these patients.However immunotherapy should be started early while the
screening of the tumour is conducted and without waiting for the results of the
antibody determinations. Many patients are initially treated with one or more of the
following, intravenous immunoglobulin, corticosteroids or a combination of them.
Patients with onconeural antibodies rarely improve with these therapies but some
stabilize.Whether these patients require more aggressive immunotherapy is
questionable and should depend on the functional status of the patient at the time.Up
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to 80% of patients with encephalitis associated with antibodies against neuronal
surface antigens respond to first line treatment. For non-responders, second-line
immunotherapy, with rituximab, cyclophosphamide or both, is recommended by
experts. There is no data on the value of long-term immunotherapy to prevent
relapses in anti-NMDA receptor encephalitis.
PROGNOSIS
Prognosis will depend of the type of encephalitis. Patients with LE, positive
onconeural antibodies and cancer rarely improve but the LE stabilizes, usually with
severe deficits, after several weeks despite appropriate immunotherapy and treatment
of the tumor. Patients with encephalitis associated with antibodies against surface
antigens, that are probably responsible for the syndrome, usually improve with
immunotherapy. Clinical recovery is particularly significant in patients with
idiopathic LE associated with anti-LGI1 antibodies and with anti-NMDA receptor
encephalitis provided early treatment is started and the underlying ovarian teratoma,
if present, removed. In patients with LE associated with anti-AMPAR antibodies or
with anti-NMDA receptor encephalitis, relapses are not uncommon particularly in
patients without cancer12,13
CASE REPORT
Name : EH
Age : 9 years
Sex : Female
Date of Admission : October, 21th 2014
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History : - This was experienced since one month ago before
admitted to HAM general Hospital. before patient has the
ability as a child his age.
- loss of consciousness preceded by convulsions 1 month ago.
with a frequency of 1 times, long seizure 20 minutes, after a
seizure patient is conscious. then the patient was taken to
Tanjung Pinang hospital by a pediatrician and treated for 2
days.
- After 2 days, the patient seizure at home. Seizure is the
whole body, while seizures eyed up, hands and feet
pounding. frequency of 10 times, a long seizure 2 minutes,
after a seizure she like confusion.
- Not preceded by febrile seizures.
- ough was not found. History of contact with old cough is not
found.
- Diarrhea was not found. Defecation and urination were
positive and normal.
- Defecation and urination were positive and normal.
- History of any family members having the same cases was
negative.
- The patient was the former patient of Infection Unit HAM
general hospital
Birth History
Spontaneous, normoterm ( 38 weeks), attended by midwives, BW 3000 gram, BL
50 cm, cyanotic (-).
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Immunization History
Hepatitis B, BCG, DPT, polio and measles vaccination were complete.
Feeding History
From birth to 6 months : Breast milk only
From 6 months to 2 years : Breast milk only + Rice porridge only
After 2 years : Family menu
Physical Examination
Generalized status
Body weight: 22,0 kg, Body Height: 125 cm
Weight for age : 75% (mild)
Height for age /age : 93% (normal)
Weight for Height : 91% (normal)
Presens status
Consciousness: Apathetic, Body temperature: 36,8oC, RR: 20 tpm, HR: 96 bpm, BP:
110/70 mmHg, Anemic (-); Icteric (-); Cyanosis (-); Edema (-). Dyspnea (-).
Localized status
Head : No deformities
Eye : Pupil diameter 3 mm . Conjunctiva palpebra inferior pale (-) Icteric sclera (-)
Light reflex (+).
- Trachea midline
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Thorax : Symmetrical fusiform and Chest retraction (-)
HR :96bpm, regular, murmur (-)
RR :20tpm, regular, rales (-)
Abdomen : Soepel, normal peristaltic, liver unpalpable, spleen unpalpable.
Extremities : Pulse 96 bpm, regular, adequate pressure and volume, warm, CRT < 3.
Urogenital : Female; within normal limit
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Renal Function Test
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Head CT-Scan interpretation:
- Hypodens lession in nc lentiformis sinistra aspek distal (diameter 0,3 cm) suspect
lacunar infark, dd : encephalomalacia (post infection ??)
- Sinusitis sphenoidales
Differential Diagnosis:
- Autoimmune enchepalitis
- Infection Enchepalitis
Working Diagnosis:
- Autoimmune enchepalitis
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Management:-
Diagnostic Planning:
- MRI
- Cek Elektrolit lengkap
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FOLLOW UP
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Urogenital : Female; within normal limit
A - Autoimmune enchepalitis
- Infection enchepalitis
P Management:
- Paracetamol 250 mg (k/p)
- Inj. Ranitidine 20 mg/8 h/iv
- Inj. Methilprednisolon 675mg in 200 cc NaCl 0,9% (in 2 hours)
- Diet MB 1540 kcal with 45 grams protein
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Eye : Pupil diameter 3 mm . Conjunctiva palpebra inferior pale (-) Icteric sclera (-)
Light reflex (+). Ear, nose and mouth were within normal limit
Neck : - Lymph node enlargement (-) Trachea midline JVP (R-2 cmH20)
O Sens: Compos mentis, Temp: 36,9oC Body weight: 22 kg, Body length: 125 cm
Head : No deformities
Eye : Pupil diameter 3 mm . Conjunctiva palpebra inferior pale (-) Icteric sclera (-)
Light reflex (+). Ear, nose and mouth were within normal limit
Neck : - Lymph node enlargement (-) Trachea midline JVP (R-2 cmH20)
Thorax : Symmetrical fusiform and Chest retraction (-)
HR :90 bpm, regular, murmur (-)
RR :24 tpm, regular, rales (-)
Abdomen : Soepel, normal peristaltic, liver unpalpable, spleen unpalpable.
Extremities : Pulse 96 bpm, regular, adequate pressure and volume, warm, CRT < 3.
Urogenital : Female; within normal limit
A - Autoimmune enchepalitis
- Infection enchepalitis
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P Management:
- Prednison 1 mg/kgBW/24 hours on 3 dose = 2:2:1
- Abilify Pulvis 1x1 mg for 7 days
- Paracetamol 3x500 mg
- Diet MB 1540 kcal with 45 grams protein
The patient was discharged in 1st of November 2014, with ability to speak and
movement is better. Treatment
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DISCUSSION
The disease mainly affects young people, with around 30% of cases under 18
years of age. Women are affected more often than men. This patient is young women
9 years old.
Autoimmune encephalitis (AE) can produce a very wide range of neuro-
psychiatric symptoms. Some patients initially present with either neurological or
psychiatric symptoms, further complicating diagnosis. Symptoms associated with AE
can include: involuntary movements slowed or blurred speech or loss of ability to
speak seizure paranoid thoughts. This patient couldnt communicated, seizure,
movement disorder, loss of ability to speak, and sometimes paraniod thoughts as the
symptoms associated Autoimmune encephalitis.
SUMMARY
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REFERENCES
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Department of Geriatrics, Russells Hall Hospital Pensnett Road, Dudley, West
Midlands. 2012:1-6
2. Pruss, H., Dalmau, J., Harms, L., et al., 2010. Retrospective analysis of NMDA
receptor antibodies in encephalitis of unknown origin. Neurology 75 (19): 17359
3. Gable, M. S., Sheriff, H., Dalmau, J., et al., 2012. The Frequency of Autoimmune
N-Methyl-D-Aspartate Receptor Encephalitis Surpasses That of Individual Viral
Etiologies in Young Individuals Enrolled in the California Encephalitis Project.
Clinical Infectious Diseases 54 (7): 899904.
7. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, et al. (2008) Anti-
NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
Lancet Neurol 7: 1091-1098
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for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with
ovarian teratoma. Acta Neuropathol 118: 737-743.
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