Presentation on theme: "A 17-year-old girl with behavior change for more than 3 weeks 高雄長庚小兒神經科 Case Discussion 2."— Presentation transcript:
A 17-year-old girl with behavior change for more than 3 weeks 高雄長庚小兒神經科 Case Discussion 2
General Data Birth: 1992-4-21 Admission: 2009-3-27 Discharge: 2009-5-15 Occupation: overseas student (Canada)
Chief Complaint Behavior change for more than 3 weeks, followed by deteriorated consciousness
History summary 2-13 2-20 behavior change, 在電腦視訊時搖頭晃腦, 說話不 流利, 答非所問, 父母親覺得變了一個人 Headache, ever went to LMD, but no improvement 3-4 Unusual behavior persisted and aggravated, so she was brought to the ER of Kelowna General Hospital at Canada. 3-6 ~ 3-7 Fever 3-8 ~ 3-11 impressed as acute psychosis or drug addiction, and admitted at psychiatric ward, then isolated
History summary 3-11 Due to fever, and refractory to too much sedation medication, such as haloperidol, she was re- evaluated with organic cause. Transferred to PICU due to deteriorated consciousness level Persisting fever combined with abnormal movement consisting of decerebrated type posturing of arms, flailing of legs and facial movements (orofacial dyskinesia). Intubation was done due to unclear consciousness. Hypoventilation was also noted.
Twice brain MRI both were normal. CSF study was also performed twice at 3-12 and 3-23. 3-12 (about 9 days after fever onset), CSF data: clear with no xanthochromia, WBC 157 (99% lymphocytes), RBC 1, glucose 3.7 (60% of serum) and protein 0.18. 3-23 CSF data: clear with no xanthochromia, WBC 69 (99% lymphocytes), RBC 1, glucose 4.0 and protein 0.21. Herpes simplex virus PCR and Gram stain are negative. Additional viral studies and fungal and TB studies are pending then, but all negative except HSV B virus. The following data were negative or within normal limits : rheumatoid factor, ANA, C3, C4, lactic acid.
CRP 45mg/L (normal is less than 10 mg/L). ESR: 35 mm/hr Random glucose, Creatinine, Uric acid =>all Normal Total protein, albumin, Alk-phosphate, AST: 19 U/L, gamma GT 14, Calcium, ionized calcium, phosphate, TSH, and beta-HCG (pregnancy test) less than 2 IU/L Urinalysis: normal Urine drug level of narcotics, such as ecstasy, methadone, cocaine, methamphetamine, amphetamine, cannabis, opiates, barbiturates and tricyclates => all negative ANCA, anti-glomerular base antibody => pending
EEG 3-day-continuous monitoring (with and without propofol) showed: diffuse slowing (1.5 to 2.5 Hz) and occasional 4 Hz with no focal nor epileptic discharge. Repeat EEG a few days later in PICU for 24 hours showed no discharge. Ultrasound of the ovaries => normal CT scan of chest, abdomen and pelvis was all normal.
Dilantin was prescribed for seizure control Acyclovir 700mg iv q8h Frequent sedation with propofol and midazolam IVIG was also prescribed: 1.5g/kg * 1 dose (needs another 0.5g/kg in Taiwan)
History summary She also had seizure at Canada PICU: –head forcibly deviated up and her eyes deviated to the right. –Duration: 10 to 20 minutes –decreased level of conscious Transferred back to Taiwan on 2009-3-27.
Past History –no specific systemic disease –no congenital disease –no bleeding tendency –no G6PD deficiency Personal History –Allergy: no known allergy –vaccination: as scheduled –To study at Canada for 5 months (since October 2008) Family History –No hereditary disease or similar disease among close family members
Physical Examination T:39.7/ ℃ P:116/min R:27/min BP:122/84 mmHg BH:160cm (50-75th percentile) BW:70kg (>97th percentile) Consciousness: eye following ok HEENT: Head: no trauma, no deformity Conjunctiva: not pale Sclerae: not icteric Throat/Tonsil: not injected Lip : laceration wound at lower lip Neck: supple, lymph node not enlarged, tracheostomy in situ
Physical Examination Chest: symmetrical expansion, no retraction, supported by ventilator BS: coarse, bilateral rales, no wheezing HS: regular heart beat without obvious murmur Abdomen: soft and flat, no tenderness, no muscle guarding Bowel sound: normoactive Ext: freely movable, no edema, flailing a 3X5 cm wound over left lower leg Other finding: no skin rash
Course and treatment 3/27 -Initial ventilator setting: PCPPV, FiO2: 50%, MR: 16/min, P: 23/5 cmH2O -IVIG 0.5g/kg -Basic workup: CBC, biochemistry, CA-125, CEA, AFP, => only CEA was mild elevated: 5.54 ng/mL (normal < 5) -Propofol line: 25 mg/hr since 3/27 -Antibiotics with Teicoplanin and rocephine -Dilantin 100mg q8h iv on 3/27, then shift to 250mg q8h on 3/28, then shift to 100mg po q8h -extremities hyperkinesia, athetoid, ballastic movement (+), orofacial dyskinesia 3/28Acycovir 700mg ivf q8h for 7 days
Course and treatment 3/28-consult infection specialist => repeat viral serology: HSV, CMV, EBV, influenza, mycoplasma, toxoplasma =>only mycoplsma IgM equivocal(10.1 BU/mL) -consult immune =>suggest IVIG or methylprednisolone pulse =>MP pulse on 4/1~4/3: 1g/kg * 3 days =>2nd IVIG treatment 2g/kg IVD in 48 hours on 4/13 to 4/15 -consult nephrologist for plasma exchange -consult endocrinologist -patient still had orofacial dyskinesia, limbs hyperkinesia, and much saliva -prescribe Valium (2mg) 1# q6h
Course and treatment 3/29CSF study: PROTEIN 15 mg/dL, WBC 11/CMM, RBC 2/CMM, NEUTROPHIL 0, LYMPHOCYTE 98, MONOCYTE 2, GLU 72 mg/dL, LACTATE 14.5 mg/dL 3/30 Abd echo: r/o left renal parenchymal disease 3/31-MRI of pelvis: Bilateral ovarian follicular cysts Swelling left internal obturator muscle Abnormal signal and enhancement of bil. internal obturator and left adductor muscles, nature? Myositis is suspected. -check C3, C4, ANA, anti-dsDNA AB => all negative
Course and treatment 4/1-Methylprednisolone pulse therapy on 4/1,2,3 -Consciousness fluctuating -Responsive to environment, family -Eye traction to object => fluctuating 4/2 -try ventilator and O2 mask (9:00 to 21:00) alternatively - 國防醫學院 預防醫學所 : HSV B ( 猴泡疹 ) IgG strong positive, IgM almost negative => send CSF for HSV B PCR on 4/8 => send paired serum on 4/15 to 疾管局 -Video EEG: abnormal record showed cortical dysfunction 4/4 DC ventilator
Course and treatment 4/10 -DC O2 use -Patient's consciousness fluctuating, not completely recovered 4/13~ 4/15 -IVIG treatment: 2g/kg IVD in 48 hours -No prominent improvement after IVIG treatment 4/16 -Aggravated irritibility (+) -Hyperkinesia mildly subsided, and sleepy in recent 2 days 4/18 -Irritibility increased -consciousness fluctuating -intermittent extremities hyperkinesia, athetoid, ballastic movement (+), still orofacial dyskinesia
Course and treatment 4/21-extremities hyperkinesia and orofacial dyskinesia subsided - 會寫自己的名字, 可點頭搖頭, 可自行翻身, 罵髒話 - consciousness still fluctuating 4/24-Consciousness alert -stands up today, and wants to walk to the toilet -wants to remove tracheostomy -mild irritable, but can understand our words and reply in some meaningful words -request 冷飲, 刨冰, and drinks smoothly, without choking -No more desaturation or dyspnea. fever subsided 5/8 Transfer to ward, then discharge on 5/15
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Lancet Neurol 2008; 7: 1091–98 Josep Dalmau MD
Summary (I) Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titers were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters.
Summary (II) Median age: 23 years (range 5–76 years); 91 were women. All presented with psychiatric symptoms or memory problems; 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 76 seizures, 69 autonomic instability, 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumors, most commonly ovarian teratoma.
Summary (III) Patients who received early tumor treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients.
Findings 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titers. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA- receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal.
Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.
Introduction (I) NMDA(N-methyl-D-Aspartate) receptors are ligand- gated cation channels with crucial roles in synaptic transmission and plasticity. The receptors are heteromers of NR1 subunits that bind glycine and NR2 (A, B, C, or D) subunits that bind glutamate. NR1 and NR2 combine to form receptor subtypes with distinct pharmacological properties, localization, and ability to interact with intracellular messengers. Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.
Introduction (II) recently identified a disorder, designated anti- NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome. The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support.
Introduction (III) Despite the severity of the disorder, patients often recovered after tumor removal and immunotherapy, suggesting an immune- mediated pathogenesis. Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors. However, selective disruption of receptors containing NR2B, which are predominantly expressed in the forebrain and hippocampus, would not explain the extensive deficits of patients.
Introduction (IV) We postulated that the crucial epitopes were present in the more widely expressed NR1 subunit. If the antibodies were pathogenic we reasoned that their effects on NMDA receptors would be reversible because most patients recover. We report the clinical features of 100 patients. We also investigate the epitopic region of the NMDA receptor and how antibodies affect NMDA receptors in primary cultures of hippocampal neurons.
Methods (I) Patients and procedures Clinical information was obtained by the authors or provided by referring physicians. Control samples were obtained from 20 healthy individuals and 230 patients with suspected autoimmune or paraneoplastic encephalitis, or patients with tumors without encephalitis examined during the period of this study. All patients had brain MRI, radiological screening for a systemic neoplasm, and serological or CSF studies that ruled out other disorders.
Methods (II) Serum and CSF were tested for antibodies against the NMDA receptor, and considered positive if 3 immuno- histochemical criteria were fulfilled. Antibody titers were measured with ELISA on HEK293 cell lysates ectopically expressing NR1 or NR1– NR2B heteromers.
Figure 1. Sera and CSF from all patients’ with anti-NMDA-receptor encephalitis showed identical antibody reactivity in 3 different assays. Coronal section of rat brain incubated with a representative CSF (A) shows intense reactivity predominantly involving the hippocampus. Cultures of non-permeabilized live rat hippocampal neurons (B) incubated with the same CSF show extensive cell-surface immunolabelling. HEK293 cells transfected with NR1 and NR2B (forming NR1–NR2B heteromers of the NMDA receptor) show intense reactivity with patients’ CSF (C); this reactivity co-localizes (D) with the reactivity of a monoclonal rabbit antibody against NR1 (E).
Methods (III) Neurological outcome was assessed with the modified Rankin scale (MRS) and mini-mental state examination (MMSE). Patients were described as having full recovery if they returned to their jobs (MRS 0, MMSE 29– 30); mild deficits, if they returned to most activities of daily living and remained stable for at least 2 months (MRS 1–2; MMSE >25–28); and severe deficits for all other cases. HEK293 cells.
Methods (IV) To determine the location of the main epitope region, we took advantage of the property of NR1 to stably assemble homomers, and of a modified NR1 subunit (NR1d4), in which amino- acid residues 25–380 are deleted but which still assembles with NR2B. To determine the effects of patients’ antibodies on the number of NMDA-receptor clusters, neurons were incubated with either patients’ or control CSF applied daily from day 7 to day 14 in vitro.
Methods (V) Each day, 20 μL of the 300 μL total medium was replaced with 20 μL of CSF. In parallel, neurons were incubated with patients’ CSF from day 7 to day 10 followed by incubation with control CSF from day 10 to day 14. On day 10 or day 14, neurons were washed, fixed, permeabilised and immunostained.
Statistical analysis done with SAS 9.1 See the original journal.
Results (I) 86 patients: headache, low-grade fever, or a non-specific viral-like illness within 2 weeks before hospital admission. 77 patients: psychiatric symptoms, including anxiety, agitation, bizarre behavior, delusional or paranoid thoughts, and visual or auditory hallucinations. 23 presented with short-term memory loss or seizures alone or associated with psychiatric manifestations.
Results (II) During the first 3 weeks of presentation, 76 had seizures. 88: decreased consciousness, progressing to a catatonic-like state, with periods of akinesis alternating with agitation, and diminished or paradoxical responses to stimuli (eg, no response to pain but resisting eye opening). Some patients mumbled unintelligible words or had echolalia. Eye contact or visual tracking was absent or inconsistent. During this clinical stage, large proportions of patients developed dyskinesias, autonomic instability, and central hypoventilation (median time of ventilatory support, 8 weeks; range 2–40 weeks).
Results (III) Orofacial dyskinesias - the most common: grimacing, masticatory-like movements, and forceful jaw opening and closing, resulting in lip and tongue injuries or broken teeth. Patients had cardiac dysrhythmias, including tachycardia or bradycardia, with prolonged pauses in 7 patients; 4 needed pacemakers. 52 had dyskinesias, autonomic instability, and hypoventilation, 27 had two of these symptoms, and 14 had just one; the remaining 7 developed a milder syndrome of seizures and psychiatric symptoms.
Results (IV) 92 patients had extensive EEG monitoring, 77% had generalized or predominantly frontotemporal slow or disorganized activity (delta-theta) without epileptic discharges. Of the 100 patients, 55 had increased signal on MRI fluid-attenuated inversion recovery (FLAIR) or T2 sequences; 14 of these patients had faint or transient contrast enhancement of the cerebral cortex, overlaying meninges, or basal ganglia. These findings were limited to a single area of the brain in 19 patients: 16 had abnormalities in medial temporal lobes, 2 in the corpus callosum, and 1 in the brainstem. Follow-up studies in 70 patients showed that many of those who recovered or were left with mild deficits had improved or normalized MRI.
Results (V) 14 patients had brain biopsy: findings for 2 were normal, 12 showed mild perivascular lymphocytic cuffing, and 10 microglial activation. All had negative results for neuronophagic nodules and viral assays. 58 (59%) of 98 patients had a neoplasm; 2 died before tumor assessment. All but 1 of these patients developed neurological symptoms before the tumor diagnosis (median 8 weeks, range 1–380 weeks). In 6 patients, the tumor was diagnosed after recovery from the encephalitis (56–380 months).
Results (VI) Ovarian teratoma identified with CT, MRI, or ultrasound was a common tumor type (median size 6 cm, range 1–22 cm). 8 had bilateral teratomas; 4 were synchronous, 2 had history of a contralateral teratoma, and 2 developed contralateral teratomas before recurrence of the encephalitis. All teratomas contained nervous tissue; 25 were examined for expression of NMDA receptors, and all were positive.
Results (VII) 1 boy (11 years old, without tumor) and 21 women and girls were younger than 19 years (median 15 years, range 5–18 years); 12 had an ovarian teratoma (5 with immature features), and 9 had no tumor. Metastases were identified only in 1 man with immature teratoma of the testis. Median follow-up was 17 months (1–194 months): 47 patients had full recovery, 28 mild stable deficits, 18 severe deficits, and 7 died as a result of the neurological disorder.
Results (VIII) Tumor was identified and removed within the first 4 months of the onset of the neurological disease →had better outcome. The median time from symptom presentation to initial signs of improvement was 8 weeks (range 2–24 weeks) for the group of patients with early tumor treatment, 11 weeks (4–40 weeks) for the group whose tumor was treated late or not treated, and 10 weeks (2–50 weeks) for the group without tumor.
Results (IX) The median duration of hospitalization was 2.5 months (range 1–14 months). While hospitalized, 7 patients had high levels of serum creatine kinase, 6 developed pulmonary embolism, 6 transient aphasia, 4 hemiparesis, and 4 tetraparesis. After discharge, 64 (85%) of the 75 patients who were left with mild deficits or eventually attained full recovery had signs of frontal-lobe dysfunction including poor attention and planning, impulsivity, and behavioral dysinhibition; 20 (27%) had prominent sleep dysfunction, including hypersomnia and inversion of sleep patterns.
Results (X) 15 patients had one to three relapses of encephalitis. The median time between initial presentation and last relapse was 18 months (1–84 months). Relapses were less common in early tumor treatment (1 of 36) than in other patients (14 of 64; p=0·009), including patients whose tumor was treated late (six of 22; p=0·009) and patients without tumor (eight of 42; p=0·03). None of the patients was receiving immunotherapy at the time of the neurological relapse.
Results (XI) Analysis of the reactivity of patients’ sera or CSF against the indicated NMDA-receptor subunits or heteromers showed that antibody reactivity was not modified by changing the NR2 subunit (A, B, C, or D) and was retained by homomers of NR1. To determine whether patients had intrathecal synthesis of antibodies, we first measured the integrity of the blood–brain barrier. Of 58 patients with paired serum and CSF available, 53 had preserved integrity of the blood–brain barrier. Analysis of normalized concentrations of IgG showed that all 53 patients had higher concentrations of antibodies in CSF than in sera, indicating intrathecal synthesis of antibodies.
Results (XII) Of the 83 patients whose CSF was available, those with tumors had higher antibody titers than those without. Patients who improved had a parallel decrease of serum titers, whereas those who did not improve maintained high titers in CSF and serum. To assess the effect of patients’ antibodies on neuronal cultures, we first determined the extent of immunolabelling of NR1 (or NMDA receptor) clusters in postsynaptic dendrites. Patients’ antibodies labelled nearly all clusters of NMDA receptors.
Results (XIII) This antibody binding did not cause apoptosis. Adding patients’ IgG to rat hippocampal neuronal cultures produced a concentration- dependent decrease of the cell-surface fraction of NMDA receptors. IgG from patients with high antibody titers produced a greater decrease of NMDA receptors than IgG from patients with low antibody titers.
Discussion (I) Of 100 patients with anti-NMDA-receptor encephalitis, a disorder that associates with antibodies against the NR1 subunit of the receptor, many were initially seen by psychiatrists or admitted to psychiatric centers but subsequently developed seizures, decline of consciousness, and complex symptoms requiring multidisciplinary care. While poorly responsive or in a catatonic-like state, 93 patients developed hypoventilation, autonomic imbalance, or abnormal movements, all overlapping in 52 patients.
Discussion (II) 59% of patients had a tumor, most commonly ovarian teratoma. Despite the severity of the disorder, 75 patients recovered and 25 had severe deficits or died. This disorder largely affects young people, and its diagnosis is facilitated by the characteristic clinical picture that develops in association with CSF pleocytosis. By contrast to the consistency of the clinical picture, MRI findings are less predictable; only 55% of patients had increased FLAIR or T2 signal in one or several brain regions, without significant correlation with patients’ symptoms.
Discussion (III) Our study indicates that 41% of patients with anti-NMDA-receptor encephalitis do not have a clinically detectable tumor, and that men and children can also be affected. Therefore, although the presence of a tumor that expresses NMDA receptors likely contributes to breaking immune tolerance, other unknown immunological triggers seem to be involved. This paradigm is similar to the Lambert-Eaton myasthenic syndrome, an antibody-mediated disorder of the neuromuscular junction that can occur with or without tumor association.
Discussion (IV) In Lambert-Eaton myasthenic syndrome the presence of a small-cell lung cancer confers a poor neurological prognosis; however, in anti- NMDA receptor encephalitis, detection of teratoma is a good prognostic factor, probably because this tumor is curable. In anti-NMDA-receptor encephalitis the high prevalence of prodromal viral-like symptoms is intriguing. Direct viral pathogenesis is unlikely because extensive studies of CSF samples, brain biopsies, and autopsies were negative for viruses.
Discussion (V) Whether the prodromal symptoms form part of an early immune activation, or result from a non-specific infection that facilitates crossing of the blood–brain barrier by the immune response is unknown. The immune response eventually predominates in the nervous system as suggested by the high frequency of pleocytosis, oligoclonal bands, and intrathecal synthesis of NR1 antibodies. Patients with an underlying tumor develop more robust immune responses than those without a tumor.
Discussion (VI) A pathogenic role of patients’ Ab is suggested by the correlation between Ab titers and neurological outcome. The latter effect was reversed by removing the antibodies from the cultures, explaining the potential reversibility of patients’ symptoms. Consistent with this Ab-induced decrease in the numbers of NMDA receptors, several NMDA-receptor antagonists such as MK801, ketamine, and phencyclidine cause symptoms similar to anti-NMDA- receptor encephalitis, including psychotic behavior, signs of involvement of dopaminergic pathways (rigidity, dystonia, orofacial movements, tremor) and autonomic dysfunction (cardiac dysrhythmia, hypertension, hypersalivation). Disruption of NR1 in animals results in hypoventilation.
Discussion (VII) A characteristic feature of patients who recover from anti-NMDA-receptor encephalitis is a persisting amnesia of the entire process. This feature is compatible with disruption of the mechanisms of synaptic plasticity, thought to underlie learning and memory, in which the NMDA receptors play a key part. Recovery from this disorder is typically slow, and symptoms may relapse, especially in patients with undetected or recurrent tumors and patients with no associated tumors.
Discussion (VIII) A possible explanation for the slow recovery could be the inability of most commonly used treatments (corticosteroids, plasma exchange, IVIG) to result in a rapid and sustained control of the immune response within the CNS. For example, in a few patients whose CSF was obtained during neurological improvement, the decrease of CSF Ab titers was substantially slower than that of serum titers. 13 of 17 patients unresponsive to the above therapies, responded to cyclophosphamide (5), rituximab (6), or both (2), drugs that are effective in other immune-mediated disorders of the CNS.
Discussion (IX) Anti-NMDA-receptor encephalitis represents a new category of immune-mediated disorder that is often paraneoplastic, treatable, and can be diagnosed serologically. Future studies should clarify the best type and duration of immunotherapy, the role of prodromal events in triggering the immune response, and the molecular mechanisms involved in decreasing the number of NMDA receptors.