TABLE 1

Clinical Case Summaries

Case 1Case 2Case 3Case 4
Baseline clinical features
 Age, sex13-y-old girl14-y-old girl12-y-old girl13-y-old girl
SHANK3 mutationc.3679dupG, p.A1227Gfs*69 (pathogenic de novo frameshift in exon 21)c.3424_3425delCT, p.Leu1142Valfs*153 (pathogenic unknown inheritance frameshift in exon 21)c.4116delC; p.Thr1373Glnfs*13 (pathogenic de novo frameshift in exon 21)c.1864_1865delinsA, p.A622fs*XX (pathogenic de novo frameshift in exon 14)
 Duration of follow-up4 y4 y5 y6 y
 Neurocognitive baselineModerate intellectual disability (verbal IQ 78; performance IQ 53)Moderate intellectual disability (IQ 40)Moderate intellectual disability (IQ 55)Mild cognitive and learning disabilities (IQ 78), delayed acquisition of speech, auditory processing disorder, and fine motor issues
 Neuropsychiatric baseline and historyHappy, socially engaged child with no previous psychiatric illnessesHistory of cyclic perimenstrual mania, catatonia, and depressive episodes beginning 2 y before intractable, subacute encephalopathy ADHD ticsADHD ticsHappy, socially engaged, high-functioning child with no previous psychiatric illnesses or mood instability
 Other medical historyHistory of autoimmune thyroiditis (elevated thyroid-stimulating hormone, elevated Abs against thyroglobulin and thyroid peroxidase)Premature puberty at age 8 y treated with monthly Lupron injections from ages 8–12 yGeneralized tonic-clonic seizure (once) at 10 y
 Family historyFather with multiple sclerosis and inflammatory bowel disease brother with lupusMaternal grandmother with bipolar disorderNo relevant conditionsMaternal aunt with bipolar and maternal grandmother with mood disorder
 Age at menarche11 y 4 mo12 y11 y 10 mo12 y
Subacute neuropsychiatric symptoms at presentation
 Age at subacute onset13 y 10 mo14 y 4 mo12 y 1 mo13 y 5 mo
 Time from onset to symptomatic nadir3-wk progressive loss of bowel and bladder control followed by overnight onset of psychosisOvernight onset of severe obsessive-compulsive symptomsOvernight onset of agitation, psychosis, and insomniaOvernight onset of anxiety, severe sleep disruption, eating restriction, and eventual obsessive-compulsive symptoms
 Audiovisual hallucinationsYesYesYesNo
 Inconsolable screaming and/or cryingYesYesYesYes
 Aphasia or mutismYes, complete aphasiaNoYes, complete aphasiaYes, near complete aphasia
 Severe anxietyYesYesYesYes
 Obsessive thinkingYesYesYesYes
 InsomniaYesYesYesYes
 Loss of self-careYesYesYesYes
 Urinary retention or incontinenceYes: profound urinary retention and incontinenceYes: sporadic episodes of daytime urinary incontinence during illnessYes: sporadic incontinenceYes; profound polyuria followed by urinary incontinence
 Hyperkinetic movementsYes: akathisiaYes: athetosis 2–3 mo before neuropsychiatric onset; tremor; facial ticsYes: akathisiaYes: chorea; tremor
 CatatoniaYesYesYesNo
 OtherAggression, bowel incontinence, picaExaggerated startleParanoiaAgraphia
Diagnostics studies
 Neurologic examination at first evaluationNonfocalNonfocal, choreiform movements of toesNonfocalChoreiform hand movements and tremor
 NeuroimagingMRI of the brain with mild ventricular prominenceMRI of the brain unrevealingMRI/MRA brain, CTA of the head unrevealingMRI of the brain unrevealing
 Elevated Ab titersAntinuclear Ab + 1:80 antithyroperoxidase Ab (>830 U/mL; normal <4) antithyroglobulin Ab (208 IU/mL; normal <2)Elevation in anti–calmodulin-dependent kinase II serologyAntinuclear Ab + 1:160Antinuclear Ab + 1:320, positive histone Abs
 Other abnormal study resultsComplement C4 (low) persistent monocytosis C1q binding (elevated) thyroid-stimulating hormone (elevated) T4 alternately high and low at different intervalsBorderline (+) titer for BartonellaEEG with diffuse slowingLow complement C4 (subsequently normalized)
 Cerebrospinal studiesWhite cells, red cells, glucose, protein, IgG index, and oligoclonal bands all normalWhite cells, red cells, glucose, and protein all normal9 white cells (67% neutrophils, 33% lymphocytes; normal range 0–5 white cells) protein, glucose, IgG index, oligoclonal bands, lactate, Cryptococcus antigen, India ink, Gram-stain, enterovirus PCR, human herpesvirus 6 PCR, mycoplasma PCR, rubeola IgG and IgM, herpes simplex 1 and 2 PCR, HIV PCR, NMDA receptor Ab, and paraneoplastic Ab panel were all normalWhite cells, red cells, glucose, protein, IgG index, and oligoclonal bands all normal
 Other normal or negative study resultsNormal Ab serologies: Mayo autoimmune encephalopathy panel including NMDA receptor, antistreptolysin ONMDA receptor AbSedimentation rate, C-reactive protein, thyroid-stimulating hormone, antithyroglobulin Ab, serum immunoglobulins, C4, C3, paraneoplastic Ab panel, serum NMDA receptor Abs, angiotensin-converting enzyme, ANCA, Bartonella IgG and IgM, lysosomal and peroxisomal panel, urine oligosaccharide and mucopolysaccharide screen, and porphyrinsNormal Ab serologies: NMDA receptor, thyroperoxidase, thyroglobulin, double-stranded DNA, voltage-gated potassium channels, anti-Ro, anti-La, phospholipid, cardiolipin, and β-2-glycoprotein I, neutrophils, paraneoplastic antigens
B-cell and T-cell immunophenotyping panel, quantitative immunoglobulinsEEG unrevealingFull-body PET; pelvic ultrasoundInfectious studies: Bartonella species, Ehrlichia chaffeensis, Babesia microti, Leishmania, Lyme panel, West Nile virus, herpes simplex viruses 1 and 2, Epstein-Barr virus, syphilis, and enterovirus
Normal genetic and/or metabolic: single nucleotide polymorphism array, fragile X, urine organic acids, plasma amino acids, carnitine, ammonia, zinc, methylmalonic acid, acylcarnitine profile, urine glycosaminoglycansAbdominal US: negative results for teratomaGenetic and/or metabolic: lactate, pyruvate, ammonia, fatty acid profile, acylcarnitine profiles, amino acid profiles of urine, serum and CSF, mucopolysaccharide and oligo- and polysaccharide profiles, cytogenetic fluorescence in situ hybridization, fragile X, array comparative genomic hybridization, and mercury
EEG unrevealing
Pelvic ultrasound normal Abdominal MRI notable for mild splenic enlargement
Therapeutic interventions
 Immunotherapy regimens and responseDaily oral prednisone 2 times per wk: no improvementIVIG 2 g/kg twice accompanied by azithromycin: correlated with complete resolution of obsessive-compulsive behaviors within 4 wk; improvement beyond premorbid baseline over 2 moIV methylprednisolone 30 mg/kg per d for 3 d, then monthly for 3 moIV methylprednisolone 1000 mg daily for 3 d: language improved within 3 d
IVIG 2 g/kg monthly for 4 mo: consistent, temporally correlated improvement in neuropsychiatric symptoms with waning effect before next doseSecond dose of IVIG during “manic relapse” correlated with resolution of mood symptoms and return to baselineIVIG 2 g/kg once followed by IVIG 1 g/kg monthlyIVIG: temporally correlated with symptom improvement
IVIG 1 g/kg and IV methylprednisolone 1 g coadministration monthly (ongoing): similar to aboveMycophenolate 750 mg BID with improvement in many symptoms and multiple less severe relapses when weaned off above regimenRituximab and mycophenolate: neuropsychiatric symptoms generally maintained at baseline while on rituximab and mycophenolate but relapsed when weaned
Cyclophosphamide was used to treat refractory relapse.
Rituximab and prednisone: near baseline but with mild psychotic exacerbations while on maintenance
 Other therapeutic modifications during immunotherapy courseWeaned off risperidone and lorazepam during immunotherapyLorazepam: coadministered with a course of IVIG with immediate, marked improvementSertraline: used for obsessive-compulsive features and anxietyMultiple trials of antipsychotics, antidepressants, sleep medications, and benzodiazepines
Addition of levonorgestrel-ethinyl after 1 y of immunotherapyClonazepam: initiated as maintenance therapy after lorazepam courseAripiprazole: started for irritability and/or repetitive behaviorsSlowly weaned off all psychiatric medications after initiation of immunotherapy
Also received trazodone, vitamin D, propranolol, and melatonin for discrete periodsOlanzapine: variably stopped and started during treatment courseMethylphenidate: for ADHD, continues to take
Daily oral contraceptive: maintained through most of courseClonidine: used intermittently for sleep, ADHD symptoms
Metformin (for olanzapine associated wt gain)Lorazepam: used for agitation and catatonia, currently weaning off this medication
Clonidine: variably stopped and started to treat agitationLithium: started during most recent relapse to treat manic symptoms
Lamotrigine: started after seizureMetformin: for aripiprazole associated wt gain
Basic ADL measures at baseline, nadir, and last follow-up
 At premorbid baselineIndependent: 5 (transferring, dressing, eating, toileting, continence)Independent: 6 (transferring, bathing, dressing, eating, toileting, continence)Independent: 6 (transferring, bathing, dressing, eating, toileting, continence)Independent: 6 (transferring, bathing, dressing, eating, toileting, continence)
Dependent: 1 (bathing)Dependent: 0Dependent: 0Dependent: 0
 At symptomatic nadirIndependent: 0Independent: 2 (transferring, toileting)Independent: 0Independent: 0
Dependent: 6 (transferring, bathing, dressing, eating, toileting, continence)Dependent: 4 (bathing, dressing, eating, continence)Dependent: 6 (transferring, bathing, dressing, eating, toileting, continence)Dependent: 6 (transferring, bathing, dressing, eating, toileting, continence)
 Most recentIndependent: 2 (transferring, eating)Independent: 6 (transferring, bathing, dressing, eating, toileting, continence)Independent: 6 (transferring, bathing, dressing, eating, toileting, continence) but impulsivity warrants supervisionIndependent: 6 (transferring, bathing, dressing, eating, toileting, continence)
Dependent: 4 (bathing, dressing, toileting, continence)Dependent: 0Dependent: 0Dependent: 0
  • Ab, antibody; ADHD, attention-deficit/hyperactivity disorder; ANCA, antineutrophil cytoplasmic antibodies; BID, bis in die; C1q, complement component 1q; C3, complement component 3; C4, complement component 4; CSF, cerebrospinal fluid; CT, computed tomography; IgG, immunoglobulin G; IgM, immunoglobulin M; La, anti-La/SSB antibody; MRA, magnetic resonance angiography; PCR, polymerase chain reaction; PET, positron emission tomography; Ro,;anti-Ro/SSA antibody; T4, thyroxine T4; US, ultrasound; —, not applicable.