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Original Investigation |

Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis

Takahiro Iizuka, MD1; Juntaro Kaneko, MD1; Naomi Tominaga, MD1; Hidehiro Someko, MD1; Masaaki Nakamura, MD1; Daisuke Ishima, MD1; Eiji Kitamura, MD1; Ray Masuda, MD1; Eiichi Oguni, MD, PhD2; Toshiyuki Yanagisawa, MD3; Naomi Kanazawa, BS1; Josep Dalmau, MD, PhD4,5,6; Kazutoshi Nishiyama, MD, PhD1
[+] Author Affiliations
1Department of Neurology, School of Medicine, Kitasato University, Sagamihara, Japan
2Department of Neurology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
3Department of Neurology, School of Medicine, St Marianna University, Kawasaki, Japan
4Institut d’Investigacións Biomèdicques August Pi i Sunyer, Barcelona, Spain
5Department of Neurology, University of Pennsylvania, Philadelphia
6Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
JAMA Neurol. 2016;73(6):706-713. doi:10.1001/jamaneurol.2016.0232.
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Importance  Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown.

Objective  To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis.

Design, Setting, and Participants  A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016.

Exposures  Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed.

Main Outcomes and Measures  Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome.

Results  The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy, serious complications, ventilatory support, or prolonged hospitalization, were not associated with a poor outcome. Five patients with DCA had longer hospitalizations (11.1 vs 2.4 months; P = .002), required ventilatory support more frequently (5 of 5 vs 4 of 10 patients; P = .04), and developed more serious complications (4 of 5 vs 0 of 10 patients; P = .004) compared with those without DCA. Although DCA was reversible, cerebellar atrophy was irreversible.

Conclusions and Relevance  In anti-NMDAR encephalitis, DCA can be reversible and does not imply a poor clinical outcome. In contrast, cerebellar atrophy was irreversible and associated with a poor outcome. This observation deserves further study to confirm progressive cerebellar atrophy as a prognostic marker of poor outcome.

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Figure 1.
Reversal of Diffuse Cerebral Atrophy in Patient 4

Follow-up T2-weighted magnetic resonance imaging (MRI) shows progressive brain atrophy, which was first noted at 1.5 months and became prominent at 7 to 11 months. The last follow-up MRIs obtained at 90 months show reversal of diffuse atrophy. Note marked dilatation of the third ventricle, the anterior horn, and the cerebral sulci (yellow arrowheads) and a reversal of dilated ventricles and cerebral sulci (blue arrowheads).

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Figure 2.
Reversal of Diffuse Cerebral Atrophy in Patient 5

Follow-up T2-weighted magnetic resonance imaging (MRI) shows mild diffuse cerebral atrophy, which was first noted at 4 months and became prominent at 6 to 7.5 months. However, follow-up MRIs at 70 months show reversal of the brain atrophy. Note mild dilatation of the third ventricle, the anterior horn, and the cerebral sulci, including the Sylvian fissure (yellow arrowheads), and a reversal of dilated ventricles and cerebral sulci (blue arrowheads).

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Figure 3.
Relatively Quick Recovery of Diffuse Cerebral Atrophy in Patient 7

Initial magnetic resonance imaging (MRI) shows symmetric T2 hyperintense signals in the medial temporal lobes (asterisks). Follow-up T2-weighted MRIs show diffuse cerebral atrophy with dilatation of the cerebral sulci and the ventricle, which was seen at 1 month and became prominent at 5.5 to 8 months (yellow arrowheads). However, subsequent MRIs show reversal of the brain atrophy, which ultimately returned to baseline brain level at the 24-month follow-up examination. Note recovery of dilated cerebral sulci as well as dilated ventricles (blue arrowheads).

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Figure 4.
Progressive Cerebellar Atrophy and Partial Recovery of Cerebral Atrophy in Patient 9

Follow-up T2-weighted magnetic resonance imaging (MRI) shows development of diffuse cerebral atrophy and progressive cerebellar atrophy. Cerebral and cerebellar atrophy are seen at 2 months and became prominent at 8.5 months. Since then, diffuse cerebral atrophy partially reversed with recovery of anterior horn dilatation (light blue arrowhead), but cerebellar atrophy remained unchanged at 47 months. Note progressive dilatation of the fourth ventricle (red arrowheads) and dilated cerebellar sulci (yellow arrowheads).

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