Demographic and clinical features
The main clinical findings of the nine patients identified are summarized in Table 1. Six were female, and the median age at onset was 51 years (range, 14-65 years). Five patients had a prodromal headache, four had fever, three had severe diarrhea, and two had weight loss. The development of neurological disorder progressed for a median of 1 month (insidious in 4, subacute in 3, acute in 2). Patients develop a rapidly progressive encephalopathy characterized by cognitive disorder or memory loss (7), accompanied by sleep disorders, including insomnia and rapid eye movement sleep behavior disorder (RBD) (3) and limb paralysis (2). Examination revealed nystagmus and hyperreflexia. Tumor screening detected B-cell non-Hodgkin lymphoma in one patient (case 6), and micropapillary carcinoma of the thyroid was found during the course of the disease in another patient (case 3).
Routine blood work of all the nine patients was normal. CSF data were available for all patients; white cell counts were elevated in two patients (370 and 220×106/L, normal range, 0-8×106/L) and protein levels were elevated in four patients (549 mg/L, 2096 mg/L, 958 mg/L and 609 mg/L; normal range, 150-450 mg/L), without evidence of any infectious agents. As shown in Figure 1, anti-DPPX antibodies were also detected by immunofluorescence in nine patients (nine serums and six CSF specimens). All patients showed anti-DPPX antibody seropositivity, whereas three CSF specimens were anti-DPPX antibody positive (1:3.2, 1:10, and 1:1, respectively). Tests for other antibodies associated with paraneoplastic syndromes and autoimmune inflammatory disorders were negative in all patients, except for Patient 5, where highly positive titers of autoantibodies against the glial fibrillary acidic protein (GFAP, serum: 1:320; CSF: 1:10) were noted.
Responses to treatment
When anti-DPPX antibodies were detected, all patients received multiple immunotherapies. Five patients were administered methylprednisolone intravenously (1 g for 3 days, 500 mg for 3 days, 240 mg for 3 days, and 120 mg for 3 days), followed by 80 mg prednisolone orally (slowly tapered over 6 months to 5 mg daily). All symptoms, such as memory loss, tremor, and ataxia, showed marked improvement. However, as prednisolone was slowly tapered over 6 months to 5 mg daily, two patients experienced a relapse of symptoms (patient 9, serum titer of 1:10 before immunotherapy, serum titer of 1:32 at follow-up after 10 months). Only one patient received oral steroids due to presentation of mild symptoms that subsequently resolved, except for very slight ataxia during the heel-to-toe test. A single treatment with intravenous (IV) methylprednisolone and a course of IV Ig (0.4 g/kg/dose * 5 days), however, produced only an incomplete effect. Patients 4 and 6 who received IV methylprednisolone therapy mentioned above and a trail of tacrolimus (3 mg, bid) or rituximab (2 cycles every 3 months, each of 375 mg/m2) had substantial recovery after 6 months of follow up.
Brain MRI changes in patients with anti-DPPX antibodies
Abnormalities were reported in brain MRIs of eight patients, of which seven had abnormalities specific for encephalitis. Only one patient showed nonspecific white matter changes. Fig 2A-2C shows increased T2/FLAIR signals in the bilateral hippocampus, temporal lobe, and amygdala. T2/FLAIR signals of the right basal ganglia, thalamus, and the left centrum semiovale and extensive abnormalities in the frontal lobe and parietal lobe were revealed (Fig. 2D-2F). Changes in the functional cortical and basal ganglia regions mentioned above were very common in encephalitis, which could lead to symptoms such as cognitive dysfunction, ataxia, nystagmus, sleep disorder, mood disorder, autonomic symptoms, limb paralysis, and extrapyramidal symptoms.
Summary of anti-DPPX encephalitis syndrome spectrum
Since the disorder of anti-DPPX encephalitis was discovered, till September 2020, the number of patients reported is 44 [4, 7-16]. Combining our nine patients (a total of 53), the median age was 52 years (range 13-76 years), and 34 (63%) were male. Only three patients were aged < 18 years (13, 14, and 15 years).
As shown in Table 2, prodromal headache occurred in six patients (11.3%), weight loss in 28 patients (52.8%), gastrointestinal disorders including diarrhea, gastroparesis, constipation, and abdominal pain in 31 patients (58.5%). Cognitive disorders (74.6%) and brainstem/spinal cord disorders including abnormal eye movement, dysphagia, stiffness, dysarthria, respiratory failure, vertigo, and hyperekplexia (75.5%) were the most common main symptoms of anti-DPPX encephalitis. Other common indications included myoclonus or tremor (49.1%), mood disorders (41.5%), sleep disorders (39.6%), disautonomia (37.7%), cerebellar ataxia (34%), and psychosis (28.3%). Seven patients (12.2%) had generalized seizure attacks and two (3.8%) had limb paralysis.
The presence of tumor was identified in eight patients (one Mantle-cell lymphoma, four B-cell non-Hodgkin lymphoma, one B cell chronic lymphocytic leukemia, one breast adenocarcinoma, and one micropapillary carcinoma of the thyroid).
Patients with anti-DPPX encephalitis might have elevated white cell count and protein levels in the CSF (42.9%), however, no evidence of infectious agents was found. Tests for other antibodies associated with autoimmune inflammatory disorders were negative in most, except for two cases. In one patient, highly positive titers of autoantibodies against GFAP (serum: 1:320; CSF: 1:10) were detected, while AQP4 antibodies were found in the serum (1:375) but not in the CSF of the other patients [14].
Multiple immunotherapies were used in 45 patients (81.1%). Follow-ups were observed in 47 patients, including 8 patients without immunotherapy: 23 (48.9%) had marked improvement, nine (19.1%) had incompletely resolved issues, nine (19.1%, 6 of them treated without immunotherapy) had no improvement, and six (12.8%, 2 of them treated with no immunotherapy) patients had died. Ten patients (21.3%) had clinical relapses, most of them occurred in steroid taper. Seven of them received immunosuppressants subsequently (rituximab, cyclophosphamide, or tacrolimus); all showed clinical improvement, whereas others had poor outcomes (two died, one had clinical progression).