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Anti-NMDA receptor encephalitis – case report

Autoimmunologiczne zapalenie mózgu z obecnością przeciwciał przeciwko receptorom NMDA – opis przypadku

Monika Służewska-Niedźwiedź1, Justyna Chojdak-Łukasiewicz1, Paweł Urbanowski1, Bogusław Para-dowski1, Anna Pokryszko-Dragan1, Krzysztof Słotwiński1, Hanna Maksymowicz2, Lech Kipiński3

1Katedra i Klinika Neurologii Akademii Medycznej we Wrocławiu 2Katedra i Zakład Radiologii Ogólnej, Zabiegowej i Neuroradiologii Akademii Medycznej we Wrocławiu 3Katedra i Zakład Patofizjologii Akademii Medycznej we Wrocławiu. Oddział Neurologii z Pododdziałem Udarowym, Szpital im. T. Marciniaka we Wrocławiu

STRESZCZENIEZapalenie mózgu z obecnością przeciwciał przeciwko recepto-rom NMDA może występować jako zespół paranowotworowy lub jako forma procesu autoimmunologicznego bez obecności ogniska neoplazmatycznego. Przebieg kliniczny jest charakte-rystyczny z obecnością grypopodobnych objawów prodromal-nych oraz następujących po nich objawach psychiatrycznych, napadach padaczkowych, ruchach mimowolnych i zaburze-niach wegetatywnych. Cel pracy. Autorzy przedstawiają przy-padek 30-letniej kobiety, bez choroby nowotworowej, u której na podstawie charakterystycznego przebiegu klinicznego wysu-nięto podejrzenie limbicznego zapalenia mózgu o charakterze autoimmunologicznym, potwierdzone wykryciem przeciwciał anty-NMDA w surowicy krwi. Omówienie i wnioski. U chorej obserwowano dobrą odpowiedź na leczenie immunomodulu-jące. Pacjentka została poddana długofalowej obserwacji ze szczególnym uwzględnieniem korelacji stanu neurologicznego ze spektroskopią rezonansu magnetycznego, badaniem neurop-sychologicznym i badaniem elektroencefalograficznym biorąc pod uwagę ilościową i spektralną analizę EEG. Słowa kluczowe: limbiczne zapalenia mózgu, zespół parane-oplastyczny, przeciwciała przeciwko receptorowi NMDA

ABSTRACTAnti-NMDA receptor encephalitis was first described as para-neoplastic syndrome, but it may have an autoimmune form without tumor association. Clinical course is very characteristic with flulike prodromal symptoms followed by psychiatric symp-toms, epileptic seizures, involuntary movements and vegetative disturbances. Aim of study. Authors present a case of 30-year-old female with characteristic clinical course of autoimmuno-logical limbic encephalitis. Results and conclusion. Diagnosis was confirmed by identification of antibodies to NMDA receptor in the serum. No associated tumor was found. Immunotherapy was effective and improved the clinical outcome. Long term follow up of the patient was performed with evaluation of her neurological and neuropsychological state and their correlation with MRI spectroscopy changes and electroencephalographic results, supported by QEEG with spectral EEG mapping. Key words: limbic encephalitis, paraneoplastic syndrome, NMDA receptor antibodies

Limbic encephalitis (LE) is an inflammatory process which involves the medial part of the temporal lobes, hippocampus, amygdala, cingulate gyrus, hypothalamus, septum and the basilar area of the frontal region [1]. Neu-rological symptoms observed in LE include emotional and behavioral abnormalities (e.g. aggression, anxiety, apathy), short-term memory loss, vegetative disturbances (thermoregulation, respiration, blood pressure), and sleep disorders, as well as seizures [1,2]. Based on clinical obser-vations and autopsy results in 1968, Corellis became the first author who used the descriptive term „limbic enceph-alitis” [3]. For many years LE was associated with the growth of tumors and the presence of onconeuronal anti-bodies [4,5]. In 2000 Gultekin et al., published the results

of paraneoplastic experiments which was performed on 50 cases of limbic encephalitis and concluded that the onconeuronal antibody (anti-Hu, anti-Ma 2, anti-Ma) was found in only 30 cases. They also discovered a new anti-body in 4 specimens, which became the catalyst for further research in this area [6]. In 2007, Dalmau et al. discovered a new anti-body, directed against the intra-cellular receptor NMDA, while examining the encephalitic limbic system of a young female with an ovarian teratoma [7].

Further research revealed LE associated with the anti-body to receptor NMDA could appear auto-immunologi-cally and without being associated with any tumor [8,9]. In addition, it was discovered that pathologies produced by the new antibody were potentially reversible and that

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M. Służewska-Niedźwiedź, J. Chojdak-Łukasiewicz, P. Urbanowski et al.

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patients responded well to immunomodulatory therapy [8,9]. On the basis of 100 examined cases, Dalmau et al. have observed that limbic encephalitis caused by the anti-NMDA antibody follows a predictable course [8]. The beginning of the illness is characterized by the predomi-nance of psychotic symptoms and disorders of short-term memory and speech, which are usually preceded by influ-enza like symptoms. Within three weeks the clinical state of the patient usually worsened. Patients experienced epi-leptic episodes and progressive disorders of consciousness. In the majority of cases vegetative disorders were also observed (disturbances of respiration and heart rhythm) at the same time. Frequently this was associated with the necessity of hospitalizing the patients in the intensive care unit. A rather interesting characteristic of patients with LE caused by the anti-NMDA antibody is that they expe-rienced involuntary movements in the form of oral-facial dyskinesias as well as dystonic movements and chorea of the limbs [8,10,11].

Only half of all cases revealed any changes in the temporal lobe while using hyper-intensive signals during MRI examinations [8]. EEG showed 92% of patients had a non-specific delay in basic functions [8,10]. Examination of cerebro-spinal fluid revealed that 91% of patients had lymphocytic pleocytosis, 32% showed an increased level of protein, and 26% had the presence of oligoclonal bands. Diagnosis was confirmed by the presence of anti-NMDA antibody in serum or cerebro-spinal fluid [8,10]. Conco-mitant tumors were confirmed in 58% of cases, with the most common being teratomas of the ovaries and testicles [8]. Treatment consisted in methylprednisolone, immu-noglobulin, plasmaforesis, or immunosuppressive drugs (cyclophosphamide, azathioprine, rituximab) as well as operations to remove the tumor [8,10].

Prognosis depended on the early recognition and tre-atment of the illness, with symptoms disappearing within 1-12 months [8,10,12].

CASE REPORTA 30-year-old woman was admitted to the Neurology Department due to behavioral changes and speaking trouble. Her neurological symptoms were preceded by headaches, excessive sleepiness and lack of appetite lasting for one week. Viral encephalitis was suspected and antiviral therapy was started. Despite treatment the condition of the patient deteriorated within 2 weeks of hospitalization. Cardiac dys-rhythmia, ventilations troubles manifested themselves and the level of consciousness decreased leading to the catatonic state (the patient was mute, did not maintain eye contact, and did not respond to intensive painful stimuli). Periodi-cally patient manifested agitation as well as focal seizures of the left extremities and intense oral dyskinesias of the lips, tongue and mandible. Neuroradiological examination (CT and MRI) did not reveal any abnormalities. Cerebrospinal fluid was examined on three separate occasions and each time there was a slight pleocytosis with a predominance of lymphocytes. No anti-herpes, tick-born encephalitis, borre-leosis and HIV antibodies were found. After a month from the onset the patient was transferred to our department.

On admission the examination revealed that the patient was in a very severe state with vegetative disturbances, such as excessive sweating and cardiac dysrhythmia. Patient was conscious but with no verbal contact, she did not follow orders, she could follow objects with her eyes and uttered incorrect words. The signs of spastic tetra-paresis were present. Temporary irregular tremors of the limbs and eyelids, oral dyskinesias and intermittent dysto-nic positioning of the upper extremities were observed as well as focal seizures with secondary generalizations. MRI revealed no changes. Magnetic resonance spectroscopy revealed decreased N-acetyloaspartate/creatine (NAA/Cr) ratio in white matter of parietal lobe as well as in cortex of the posterior cingulate gyrus as the evidence of decrease neuronal activity and neuronal loss of non-specific origin (fig.1). EEG showed general slowing with predominance over the left hemisphere and paroxysmal delta waves in fronto-parieto-temporal regions that also predominated on the left side (fig.2). Spectral EEG mapping demonstrated the asymmetric focus of low-frequency (0,6—4 Hz) brain activity localized in the left frontal lobe below the F3 and F7 electrodes (fig.3a). Asymmetry of delta waves in other locations in the quantitative analysis of EEG has not been revealed (fig.4a). Laboratory tests revealed the presence of leukocytosis, anemia and elevated level of transaminases. Cerebrospinal fluid examination revealed no abnormali-ties. Additionally, no associated tumor on radiological exa-mination or during gynecological consultation was found. After autoimmune encephalitis was suspected anti-NMDA receptor antibodies was found in serum that supported the diagnosis. Treatment consisted of intravenous acyclovir, L-Dopa and antiepileptic drugs. After diagnosis of autoim-mune encephalitis, methylprednisolone 1000 mg i.v. for 5 days followed by intravenous immunoglobulins (including 99 g.) was started.

Clinical state of patient was gradually improving within two weeks after immunomodulation therapy. She started to utter simple words, followed the commands, and was auto--oriented. Psychiatric symptoms, agitation, dyskinesias and epileptic seizures resolved. Psychical state had also improved, no pyramidal signs were observed on control neurological examination.

Neuropsychological examination revealed dysfunction of: frontal lobe (verbal and motor perseverations, impa-ired abstract thinking and working memory), temporal lobe (sensory aphasia, disturbances in verbal memory) and parietal lobe (imaginative apraxia, agraphia, alexia and acaculia). EEG monitoring showed an alpha rhythm of 10 Hz over the right hemisphere and theta rhythm of 4-7 Hz over the left hemisphere intermitted with delta waves. Magnetic resonance spectroscopy revealed the metabolic composition of white matter to be normal (normal NAA/Cr ratio) and a slight decrease of neuronal activity in the posterior part of the cingulate gyrus cortex (decrease of NAA/Cr ratio and increase of choline/creatine ratio).

Further observation of the patient within a year showed the gradual improvement of her clinical status, assessed during control neurological and neurophysiological exami-nations. Regression of language disturbances, apraxia and

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Fig. 1. MR spectroscopy in a patient with anti-NMDA receptor encephalitis after one month from onset of symptoms. N-acetyloasparate (NAA)/creatine (Cr) ratio was reduced in the voxel (white box) containing the cortex of postreion cingulate gyrus.

Fig. 2. EEG in patient with anti-NMDA receptor encephalitis after one month from onset of symptoms shows general slowing with predominance over the left hemisphere.

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DISCUSSIONThe case described above confirmed the observation that encephalitis caused by anti-NMDA antibody follows a rela-tively stable or even stereotypical course [2,8]. Like in other authors’ cases, the presence of prodromal symptoms, as well as psychiatric disturbances were observed in the early phase of LE. The evolution of symptoms was also typical in our case with the worsening of the conscious state of the patient, along with epileptic attacks and vegetative disturbances. In addition, the most characteristic symptom of anti-NMDA encephalitis was also observed, namely, oro-facial dyskine-sias [2,13].

Special emphasis should be put on the sensitivity of MRI spectroscopy that revealed a decrease in the activity of the cerebral cortex and the white matter of posterior cingulate gyrus. CT and MRI, on the other hand, found no structural changes in the brain. Additionally, during

follow-up period, the disappearance of disturbances in MRI spectroscopy correlated with an improvement in the patient’s clinical state. MRI spectroscopy may be thought a sensitive diagnostic tool in LE follow-up.

Although most patients only showed non-specific chan-ges in their EEG, it remains an important diagnostic tool in aforementioned encephalitis, especially in the first phase of the disease, when psychiatric symptoms predominate and cerebrospinal fluid testing as well as neuro-radiologi-cal examination may be normal [8]. In the case presented, careful attention should be paid to the fact of asymmetry of the EEG with a predominance of pathological changes in the left hemisphere of the brain that was also shown by spectral EEG analysis [14].

In reports relating to anti-NMDA encephalitis it is emphasized that early diagnosis and prompt treatment

agnosia was observed, although some emotional and moti-vational troubles were still present. EEG showed synchro-nization of posterior dominant rhythm and disappearance of paroxysmal delta waves. QEEG revealed that the slow-

-wave amplitude asymmetry disappeared (fig.3b, fig.4b). Actually patient is on oral immunosupresion therapy (aza-thioprine) and low doses of steroids. She is still under the observation of our neurology and neuropsychology team.

Fig. 3. The 3-D topography of spectral power of EEG obtained by Fast Fourier Transform (FFT) in 3 frequency bands: delta (0,6-4 Hz), theta (4-8 Hz) and alpha (8-10 Hz). a) and b) represent absolute power amplitude in [µV2/Hz] for EEG recorde during the first and last hospitalization successively.

Fig. 4. The time and spatial variability of absolute spectral power calculated from FFT in delta frequency band: a) and b) are related to the first and last EEG examination successively; white boxes indicate left hemisphere and black boxes indicate right hemisphere. On top, the averaged spectral power for F3/4 and F7/8 electrodes; below, the averaged spectral power for other locations. Amplitude assymetry present in the first chart disappeared after several months of treatment and the energy of slow waves has been reduced in comparison with the baseline study.

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Fig. 5. EEG in patient with anti-NMDA receptor encephalitis after 2 months from onset shows an alpha rhythm of 10 Hz over the right hemisphere and theta rhythm of 4-7 Hz over the left hemisphere.

improves the prognosis [2,8]. The improvement in clinical state of our patient after methylprednisolone and immu-noglobulin administration confirmed earlier observations.

Special emphasis should be placed on the fact that despite the improvement in the patient’s clinical condition, disappearance of vegetative symptoms, epileptic attacks and involuntary movements, disturbances in higher neu-rological functions, especially of the dominant cortex were still present during the follow-up phase of hospitalization. Other authors have observed similar course with higher neurological functions disturbances and their disappe-arance within a period of 1-12 months [12].

Anti-NMDA receptor encephalitis is a rare disorder that should be taken into account in the differential dia-gnosis, especially in young women with neuro-psychiatric symptoms and progressive disturbances of consciousness, vegetative disturbances, and associated involuntary move-ments. Drawing attention to the characteristic course of the disease and typical, progressive clinical signs allows for early diagnosis and its confirmation by demonstrating the presence of antibodies against NMDA receptor in serum or cerebrospinal fluid.

REFERENCES[1] Wandinger K.P., Saschenbreker S., Stoecker W. et al.: Anti-NMDA-

receptor encephalitis: a sever, multistage, treatable disorder presenting with psychosis. J Neuroimmunol 2010; 231: 86–91.

[2] De Broucker T., Martinez-Almoyna L.: Encephalite avec anticorps anti-recepteur NMDA. Medecine et Maladies Infectieuses 2009; 40: 1–5.

[3] Corsellis J.A.N., Goldberg G.J., Norton A.R.:”Limbic encephalitis” and it’s association with carcinoma. Brain 1968; 91: 481–495.

[4] Dalmau J., Posner J.B.: Paraneoplastic syndromes affecting the nervous system. Semin Oncol 1997; 24: 318–328.

[5] Graus F., Saiz A., Dalmau J.: Antibodies and neuronal autoimmune disorders of CNS. J Neurol 2010; 257: 509–517.

[6] Gultekin S.H., Rosenfeld M.R., Voltz R. et al.: Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumor association in 50 patients. Brain 2000; 123: 148–194.

[7] Dalmau J., Tuzin E., Masjuan J.et al.: Paraneoplastic and anti-N-methyl-D-asparate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61: 25–36.

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[8] Dalmau J., Gleichman A.J., Hughes E.G. et al.: Anti-NMDA receptor encephalitis: Case series and analysis of the effects of antibodies. Lancet Neurol 2008; 79: 1091–1098.

[9] Florance N.R., Davis R.L., Lam C. et al.: Anti-N-metyl-D-asparate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009; 66: 11–18.

[10] Irani S.R., Bera K., Waters P. et al.: N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in predominantly non-paraneoplastic dis order of both sexes. Brain 2010; 133: 1655–1667.

[11] Ferioli S., Dalmau J., Kobet Ch. et al.: Anti-N-methyl- d-aspartate Receptor Encephalitis: characteristic behavioral and Movement Disorder. Arch Neurol 2010; 67: 250–251.

[12] Frechette E.S., Zhou L., Galetta S.L. et al.: Prolonged Follow-up and CSF Antibody Titers in a Patient With Anty-NMDA Receptor Encephalitis. Neurology 2011; 76: 64.

[13] Kleinig T.J., Thompson P.D., Matar W. et al.: The Distinctive Movement Disorder of Ovarian Teratoma-Associated Encephalitis. Movement Disorders 2008; 23: 1256–1261.

[14] Okamoto M., Dan H., Sakamoto K., et al.: Three-dimensional probabilistic anatomical cranio-cerebral correlation via the international 10-20 system oriented for transcranial functional brain mapping. Neuro Image 2004; 21: 99–111.

Adres do korespondencji:Monika Służewska-Niedźwiedź, Katedra i Klinika Neurologii AM we Wrocławiu, ul. Borowska 213, 50-556 Wrocław, e-mail: [email protected]

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