Characterisation and outcome of neuropsychiatric symptoms in patients with anti-NMDAR encephalitis.

BACKGROUND: Encephalitis due to anti-N-methyl-D-aspartate receptor antibodies (ANMDARE) is the most frequent immune-mediated encephalitis. It is distinguished by the subacute onset of neuropsychiatric symptoms. OBJECTIVE: To evaluate the characteristic neuropsychiatric symptoms and their outcome in patients diagnosed with ANMDARE. METHODS: This was a prospective, longitudinal study in patients with a diagnostic suspicion of ANMDARE that presented to the National Institute of Neurology from March 2018 to February 2019. A comparative analysis of two groups (positive N-methyl-D-aspartate receptor [NMDAR] vs. negative NMDAR antibodies in cerebrospinal fluid [CSF]) was done on admission and at discharge. Neuropsychiatric systematic assessments included the Neuropsychiatric Inventory Questionnaire, the Bush Francis Catatonia Rating Scale, the Confusion Assessment Method Severity, the Montreal Cognitive Assessment, and the Overt Agitation Severity Scale. RESULTS: 24 individuals were analysed: 14 had positive NMDAR antibodies, and 10 had negative NMDAR antibodies in CSF. On admission, agitation/aggression, euphoria/exaltation, and disinhibition were more common in patients with positive antibodies. Excited catatonia and delirium were diagnosed more frequently in patients with positive antibodies. At discharge, there was an important decrease in neuropsychiatric symptoms, but substantial cognitive impairment remained. The mean hospitalisation length was 41.71 (SD 39.33) days for patients with definitive ANMDARE (p 0.259). CONCLUSIONS: Neuropsychiatric symptoms profile in ANMDARE was associated with the early onset of euphoria/exaltation and disinhibition, accompanied by marked psychomotor agitation. When ANMDARE was suspected, the presence of excited-type catatonia and delirium showed a tendency to predict definitive ANMDARE. At discharged, most patients recovered from catatonia, delirium, and psychosis, but marked cognitive symptoms, anxiety, and depression persisted at discharge.

Hypothalamic abnormality in patients with inflammatory demyelinating disorders.

BACKGROUND: Hypothalamic lesions in neuromyelitis optica (NMO) patients might be more specific for NMO than multiple sclerosis (MS). However, this is controversial. OBJECTIVE: To characterize clinical features of patients with inflammatory demyelinating disorders (IDDs) with visible hypothalamic lesions using magnetic resonance imaging (MRI). METHODS: Patients with IDDs (n = 429) were recruited retrospectively. RESULTS: Of 52 patients with hypothalamic images enrolled, 42 were positive for aquaporin-4 (AQP4) antibodies, including 28 patients with NMO, 6 with recurrent transverse myelitis, 3 with recurrent optic neuritis, and 5 with brainstem and brain syndrome. The remaining 10 patients were anti-AQP4-negative, including 3 with MS, 3 with acute disseminated encephalomyelitis, and 4 with other disorders. In the AQP4-positive group, manifestations, including ataxia, intractable hiccup and nausea, syndrome of inappropriate antidiuretic hormone secretion and encephalopathy were more frequent in those with hypothalamic lesions than those without. Cell counts of cerebrospinal fluid in patients with hypothalamic lesions differed from patients without lesions. Brain MRI abnormalities were more frequent in brainstem and hemisphere of the hypothalamic lesion group. CONCLUSIONS: Hypothalamic lesions were observed frequently in patients with AQP4 antibodies. Clinical manifestations and paraclinical features in AQP4-positive patients with hypothalamic lesions differed from those without lesions.

Syndrome of inappropriate antidiuretic hormone secretion in patients with aquaporin-4 antibody.

The objective of this study was to analyze the frequency of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with positive aquaporin-4 (AQP4) antibodies and evaluate the relationship between SIADH and hypothalamic lesions in patients with NMO and NMO spectrum disorder (NMOSD). AQP4 antibodies were tested by an indirect immunofluorescence assay employing HEK-293 cells transfected with recombinant human AQP4. Clinical data of patients were analyzed retrospectively. In total, 192 patients with AQP4 antibodies were certified, of which 41 patients (21.4 %) were included in the present study. Six patients (14.6 %, 6/41) met the criteria of SIADH, of which hyponatremia was mild in one patient, and severe in five. Five patients experienced confusion or decreased consciousness. Four patients were diagnosed with NMO and two were diagnosed with recurrent optic neuritis. Magnetic resonance imaging showed 11 of 41 patients (26.8 %) had hypothalamic lesions. All patients with SIADH had hypothalamic abnormalities. Hyponatremia resolved in all patients after intravenous methylprednisolone and intravenous immunoglobulin therapy. SIADH is not rare in patients with NMO/NMOSD, especially in patients with lesions close to the hypothalamus.

Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy.

IMPORTANCE: Idiopathic narcolepsy with cataplexy is thought to be an autoimmune disorder targeting hypothalamic hypocretin neurons. Symptomatic narcolepsy with low hypocretin level has been described in Ma antibody­associated encephalitis; however, the mechanisms underlying such an association remain unknown. OBSERVATIONS: We described a 63-year-old man with clinical criteria for diencephalic encephalitis with sleepiness, cataplexy, hypocretin deficiency, and central hypothyroidism, together with brainstem encephalitis reflected by supranuclear ophtalmoparesis and rapid eye movement sleep behavior disorder with underlying abnormalities on brain magnetic resonance imaging. An autoimmune process was demonstrated by the detection of antibodies against Ma protein. Death occurred 4 months after disease onset without any tumor detected. Neuropathology, immunohistochemistry, and immunoreactivity results were compared with those obtained in idiopathic narcolepsy-cataplexy and with normal control brains. The principal findings revealed almost exclusive inflammation and tissue injury in the hypothalamus. The type of inflammatory reaction suggests cytotoxic CD8+ T lymphocytes being responsible for the induction of tissue injury. Inflammation was associated with complete loss of hypocretinergic neurons. Autoantibodies of the patient predominantly stained neurons in the hypothalamus and could be absorbed with Ma2. CONCLUSIONS AND RELEVANCE: The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons.

Cerebral folate deficiency.

Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia. Other signs may include deceleration of head growth, visual disturbances and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. Once identified, CFD can in many cases be treated by administering oral folinic acid. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency. Generation of autoantibodies against the folate receptor required to transport 5MTHF into CSF and mutations in the folate receptor 1 (FOLR1) gene have been reported to be causes of CFD. However, other mechanisms are probably also involved, as CFD has been reported in Aicardi-Goutiere's and Rett syndromes and in mitochondriopathies. Several metabolic conditions and a number of widely used drugs can also lead to a decrease in the concentration of CSF 5MTHF, and these should be considered in the differential diagnosis if a low concentration of 5MTHF is found following CSF analysis.

Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder.

Although serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive-compulsive disorder (OCD), it is unclear whether these antibodies can cross the blood-brain barrier to bind against BG or other components of the OCD circuit. It is also unclear how they might lead to hyperactivity in the OCD circuit. We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls using western blot. We further investigated CSF amino acid (glutamate, GABA, taurine, and glycine) levels and also examined the extent to which these levels were related to the presence of autoantibodies. There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. There was no significant difference in binding between patient and control sera except for a trend toward more bands to BG and thalamic protein corresponding to 43 kD among OCD patients compared with controls. CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls, and further multivariate analysis of variance showed that CSF glycine levels were higher in those OCD patients who had autoantibodies compared with those without. The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.

Chronic myoclonia of subcortical origin with antiglutamate receptor antibodies.

We report a 10-year-old girl with chronic nonprogressive continuous myoclonia with mild muscle weakness and dissociated sensory impairment of the ipsilateral side of myoclonic jerks. Irregular myoclonic jerks continuously appeared in the right upper limb. The jerk-locked back averaging of electroencephalographic activity failed to show any activity preceded by the muscle contraction. Magnetic resonance imaging of the brain and cervical spine revealed no abnormal findings. Single photon emission computed tomography showed an increased blood perfusion in the left thalamus. (18)F-deoxyglucose-positron emission tomography (PET) also showed a slight high density in the posterior region of the left thalamus. Antiglutamate receptor epsilon2 and delta2 antibodies were detected in the serum and cerebrospinal fluid. The patient's symptoms have now been stable with clonazepam treatment for 2 years. The left thalamus was suspected to have been the region at least partly responsible for the patient's symptoms.

Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.

Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum.

The serum of a patient with subacute cerebellar dysfunction was used to probe a cDNA expression library and isolate two genes: Zic1 (zinc-finger of the cerebellum) and Zic4. The patient had intrathecal synthesis of Zic antibodies, suggesting that the Zic proteins were autoantigens of the neurologic disorder. The Zic proteins are involved in cerebellar development and are reported as being preferentially expressed by medulloblastomas. It was found that the expression of Zic proteins is enriched in, but not limited to, medulloblastomas and primitive neuroectodermal tumors.