Cotard syndrome in anti-adenylate kinase 5 autoantibodies limbic encephalitis

Cotard syndrome (CS) has been reported in patients with anti-N-methyl-D-Aspartate receptor (NMDAr) autoantibodies encephalitis, but not in limbic encephalitis (LE) associated with other autoantibodies. Clinical features of LE associated with autoantibodies against adenyl kinase 5 (AK5), a specific nucleoside monophosphate kinase of the central nervous system with crucial metabolic functions, have been previously reported in the literature. However, this is the first case reporting CS as one of the psychiatric symptoms during the clinical course. A right-handed 83-year-old woman developed memory problems, disorientation, behavioral changes and visual hallucinations in the past 2 months. Over the next 4 weeks, her symptoms progressed to a more marked deterioration of spatial orientation that interfered with daily activities and hobbies. In the following 4 weeks, she started to deny the existence of her head and occasionally she referred to herself as being dead. Neurological examination showed disorientation and anterograde amnesia. The Montreal Cognitive Assessment Scale score was 12 out of 30. Anterograde memory, attention, orientation and visuospatial/executive functions were predominately affected, whereas language and abstraction domains were spared. Routine laboratory examinations were within normal limits and infectious diseases of the central nervous system were ruled out. Cerebral spinal fluid showed lymphocytic pleocytosis (34 cells/mm, 58% lymphocytes), and hyperproteinorrachia (880 mg/L), with no presence of oligoclonal bands. Standard LE autoimmunity screening in cerebral spinal fluid was negative, including anti-NMDAR autoantibodies. A cerebral spinal fluid sample was sent to a specialized neuroimmunology laboratory for further analysis. Indirect immunofluorescence on a mouse tissue composite (TIF) showed positive anti-AK5 antibodies that were later confirmed by a cell-based assay carried out on human embryonic kidney 293 transfected cells. No other autoantibodies were positive. Brain magnetic resonance imaging showed bilateral hyperintensities in the mesial temporal lobes. The electroencephalogram and body positron emission computed tomography were unremarkable. The patient received 5-day intravenous immunoglobulin in combination with intravenous methylprednisolone (1 g/day). Over the next 3 months, the clinical course was unfavorable, and she underwent two cycles of rituximab. Cotard delusion persisted despite treatment with high doses of quetiapine. To the best of our knowledge, there are 30 reported cases of LE associated with anti-AK5 antibodies, and the present case is the first to report CS as a part of the clinical features. As in this case, patients with anti-AK5 encephalitis usually present a particularly unsatisfactory response to immunotherapy. Among the reported cases, most of the patients developed dementia due to rapidly progressive memory deficits, and approximately 50% of patients developed hippocampal atrophy. It might be possible that patients with anti-AK LE must be treated with an early aggressive immunotherapy approach to improve the prognosis, but there is not enough evidence regarding alternative treatment strategies. CS is a nihilist delusion ranging from denial of the existence of a body part to negation of self-existence. Since its first description in 1880, it has been traditionally considered a pure psychiatric syndrome. Regarding neurological diseases, CS has been documented in patients with anti-NMDAr encephalitis. It has been suggested that anti-NMDAr antibodies could mediate the development of CS by direct damage to the NMDAr synaptic networks. However, the present case confirms that CS can develop in LE mediated by other autoantibodies as a result of damage to limbic structures and not to a specific antibody. Delusional symptoms should be actively looked for in patients with LE.