Anti-N-Methyl-D-Aspartate Receptor Encephalitis Causing a Prolonged Depressive Disorder Evolving to Inflammatory Brain Disease
In June 2012, a 32-year-old woman was referred to our clinic to investigate a progressive cognitive dysfunction, cerebellar ataxia, abnormal movements and a reduced word output. She had a 9-month history of slowly progressing mood changes and ‘brain fog’. The patient was a high school teacher, with an unremarkable medical history, who lived with her husband and 20-month-old son. Five months earlier, she had attended a psychiatric clinic where she received a tentative diagnosis of postpartum depression. Antidepressants and benzodiazepines left her clinical condition unchanged. Thereafter, while under psychiatric care, the patient slowly began to experience hypersexuality, dysarthria, imbalance, decreased word output and episodes of unexplained crying. EEG tracings at that time showed diffuse slowing without epileptiform activity. Upon referral to our clinic, a brain MRI disclosed widespread multifocal lesions, hyperintense on T2-weighted images, involving the brainstem, the thalamus, the caudate and lenticular nuclei, the insula and the corona radiata. Two periventricular lesions and several small spots in the insula and pyramidal tract showed a contrast enhancement. Given the clinical and MRI findings, the patient was admitted for further investigation.\nOn examination, the patient was alert. Her speech was dysarthric, hypophonic and she answered in short phrases. Cognitive testing disclosed a markedly impaired executive function. Color vision testing detected dyschromatopsia and visual field testing found full visual fields on confrontation. Saccades were hypometric and slow with upward palsy. She had postural instability, an ataxic gait, dysmetria, oro-lingual facial dyskinesias, choreoathetosis, hand dystonia and mild muscle rigidity. Deep tendon reflexes were brisk with bilateral ankle clonus. Hematologic and serum chemical tests, including a screening for rheumatologic diseases and a comprehensive panel for infectious, metabolic and paraneoplastic disorders yielded negative findings. The whole-body PET scan was unremarkable. Upper and lower limb somatosensory and motor evoked potentials elicited slightly reduced amplitudes on the left side; conversely, flash-evoked visual potentials showed prolonged N2 and P2 latencies (fig. ). Cerebrospinal fluid (CSF) analysis, including tau protein level and a 14-3-3 protein assay yielded normal findings, except for an elevated IgG index and oligoclonal IgG bands; we detected anti-NMDAR IgG antibodies. CSF cell count showed 1 white cell per milliliter and nucleic acid testing for HSV, VZV and enteroviruses was negative. In addition, testing of serum and CSF for water channel protein aquaporin-4-IgG-Ab by indirect immunofluorescence was negative. The positive CSF anti-NMDAR and negative serum findings were also confirmed elsewhere using human embryonic kidney cells expressing the NR1 subunits (Dr. Josep Dalmau, Hospital Clinic, Universitat de Barcelona, Spain). In July 2012, a brain scan using a 3T MR scanner detected multiple and partially confluent punctate foci of T2/FLAIR hyperintensity, unenhanced after gadolinium, bilaterally in the basal telencephalon, diencephalon, external capsulae, subcortical insula, periventricular white matter, temporal horns, corpus callosum, and optic nerves as well as the ventral cerebral peduncles, pontine-mesencephalic junction and dorsal pons (fig. ). Spectroscopy of the left basal ganglia region and the right midbrain tegmentum, acquired with the single-slice multi-voxel chemical-shift technique (TE = 30 and 135 ms), showed a reduced N-acetyl aspartate (NAA) peak and a slightly increased choline (Cho) peak, resulting in an inverted Cho/NAA ratio, in addition to lipid traces and an absence of lactate within a high signal-intensity foci.\nThese brain metabolic findings were consistent with widespread encephalitis, characterized by confluent bilateral demyelination areas and focal optic nerve involvement in a late subacute stage. The patient was treated with oral corticosteroids followed by two IVIg cycles, given at 2-week intervals, in August 2012. After treatment, the gait ataxia improved and her mood improved, but the EEG tracings were unchanged. At neuropsychological evaluation, working memory, attention, and the logical-deductive capacities remained altered; the Mini-Mental State Examination score was 26/30. Between August and November 2012, the patient received 4 IVIg cycles given at 4-week intervals.\nIn November, a repeat MRI scan showed a reduction in the number and the extension of lesions previously described, with a new, non-enhancing lesion in the left basal ganglia. Thereafter, therapy was switched to cyclophosphamide. In December 2012, neurological evaluation showed a slight improvement of speech, ataxia and cognitive function; dystonic posturing of the left hand, slight postural tremor of the left limbs, brisk reflexes, muscle rigidity in the lower limbs and oro-lingual dyskinesias were observed. In March 2013, brain MRI showed that most alterations had disappeared and residual lesions were no longer contrast enhanced (fig. ). A PET brain scan showed a reduced glucose metabolism in the temporal lobes and the left striatum, relative to other cortical areas (fig. ).\nAt the last visit in August 2013, cognitive function, speech and balance had improved, but emotional liability and her attention deficit persisted.