To the Editors
Anti-DPPX (dipeptidyl-peptidase-like protein-6) encephalitis, discovered in 2013, is a rare autoimmune disorder affecting the central nervous system (CNS), characterised by a range of neurological and gastrointestinal symptoms. The disease is caused by antibodies targeting DPPX, a regulatory subunit of Kv4.2 potassium channels, which are crucial for controlling neuronal excitability. DPPX is expressed in various brain regions, including the hippocampus and cerebellum, as well as in the myenteric plexus of the gastrointestinal system. The widespread distribution of the receptors explains the multifocal disease manifestations. The disruption of these potassium channels by anti-DPPX antibodies leads to a cascade of symptoms, which are both neurological and gastrointestinal in nature [1, 2].
Early signs of anti-DPPX encephalitis often include unexplained weight loss and gastrointestinal disturbances, particularly severe diarrhoea. These symptoms are typically followed by a range of neurological issues, including cognitive dysfunction, agitation, hallucinations, and exaggerated startle responses. In addition to these neuropsychiatric symptoms, patients may experience motor disturbances such as resting tremors, rigidity, myoclonus, and even seizures. Sleep disorders such as REM sleep behaviour disorder, are also common. Most patients are middle-aged, with a median age at onset of c.52 years, and men appear to be more frequently affected than women. Diagnosis is confirmed by identifying anti-DPPX autoantibodies in the patient’s blood or CSF [1, 2].
The disease typically progresses subacutely over several months, which can make an early diagnosis challenging. Anti-DPPX encephalitis has often been misdiagnosed as other conditions, such as Creutzfeldt-Jakob Disease (CJD), due to overlapping symptoms such as cognitive decline and myoclonus. However, unlike CJD, anti-DPPX encephalitis is a treatable condition, especially when identified early. Immunotherapy, including corticosteroids, intravenous immunoglobulin, plasmapheresis, azathioprine, rituximab, cyclophosphamide, and mycophenolic acid has shown promise in managing the disease and improving outcomes for patients. Anti-DPPX encephalitis may be associated with malignancy in up to 10% of cases, most commonly B-cell lymphoma, although cases related to small cell lung cancer, breast cancer, and hepatocellular carcinoma have also been described [1–6].
A 54-year-old Caucasian woman without a history of chronic diseases was admitted to hospital for evaluation of rapidly progressive cognitive deficit. 18 months before admission, she experienced persistent diarrhoea lasting for about two months, loss of appetite, and a weight loss of c.10 kg. The patient was diagnosed with erosive gastritis and helicobacter pylori infection, and her symptoms subsided after treatment.
After a few months, the patient became apathetic, had memory problems, and her mood slightly deteriorated. She consulted a psychiatrist, who diagnosed her with depression and started treatment, which was ineffective. She was hospitalised twice in the psychiatric ward, without improvement. At that time, she exhibited slowed speech and disorientation — she wandered around the department and required constant supervision by staff, with a progressive decline in cognitive function being observed. Balance issues and eating disorders also appeared: the patient refused meals but consumed a lot of sweets, which she had previously disliked, and smoked heavily. Over the following months, the patient was hospitalised several times in the psychiatric, internal medicine, and neurology departments. Brain MRI showed non-specific demyelinating changes, and a cerebrospinal fluid examination returned normal results. A salivary gland tumour was diagnosed, with a biopsy result suggesting cancer, requiring further evaluation after the tumour’s removal. No surgery was performed due to the patient’s condition.
Neurological examination upon admission to our department: conscious; non-verbal; does not follow commands; reacts with fear during examination; significantly increased rigidity of all four limbs and trunk; pupils round, equal, and symmetrically reactive to light; bedridden; and cachectic.
During this stay, EEG and brain MRI were performed. In the EEG, periodic discharges of triphasic sharp wave complexes and background slowing were recorded (Fig. 1). Brain MRI, performed twice, revealed non-specific, small vascular lesions, progressive subcortical brain atrophy, and a tumour of the right salivary gland (Figs. 2, 3). In two cerebrospinal fluid tests, normal general parameters were obtained: clear, WBC count 3 (normal range 0–5), RBC count 0, protein 13.6 mg/dL (normal range 20–40), glucose 3.42 mmol/L (normal range 2.20–4.16). Immunophenotyping showed no sign of a proliferative process. The presence of oligoclonal bands was detected. Due to the EEG findings, cerebrospinal fluid was tested for Creutzfeldt-Jakob Disease: the RT-QuIC test was negative, and no presence of the 14-3-3 protein was detected in cerebrospinal fluid using the Western blot method. However, anti-DPPX antibodies were detected using the indirect immunofluorescence method at a titre of 1:32 and were tested only in CSF.
Chest and abdominal CT scan showed enlarged axillary lymph nodes with strong enhancement after intravenous contrast administration. A biopsy was postponed due to the patient’s neurological condition.
Due to elevated cancer markers, the patient was gynaecologically and oncologically consulted. No malignancy was found, except for the salivary gland tumour. The salivary gland tumour was removed, and histopathological examination revealed acinic cell carcinoma.
Based on the clinical presentation and additional test results, autoimmune encephalitis with anti-DPPX antibodies was diagnosed. Intravenous treatment with methylprednisolone (1 g/day for five days) and immunoglobulins (18 g/day for five days) was administered, but no neurological improvement was achieved. Subsequently, treatment with rituximab (five doses of 375mg/m2 for seven days) was initiated. Over the following days, the patient’s neurological condition showed a slight improvement — she began to utter single words, follow simple commands, and eat some parts of the meals she was offered.
Anti-DPPX encephalitis typically presents with a subacute to chronic onset of encephalopathy, along with hyperkinetic movement disorders and myelopathy, often preceded by prodromal diarrhoea. Less common manifestations include neurological conditions such as opsoclonus-myoclonus syndrome, progressive encephalomyelitis with rigidity and myoclonus, and stiff-person syndrome. Diagnostic tests tend to produce nonspecific and variable results. Brain MRI might show increased signal on T2/fluid-attenuated inversion recovery sequences in temporal lobes. CSF examination may reveal increased protein, mild pleocytosis and positive 14-3-3 protein. EEG is abnormal in the majority of patients, showing e.g.. slow background, triphasic periodic complexes, and epileptiform discharges. Autoimmune encephalitis (AE) can manifest primarily as significant cognitive impairment, even in the absence of clear inflammatory changes on MRI or in cerebrospinal fluid. Cognitive decline may also be observed in encephalitis other than anti-DPPX-related cases, including anti-NMDAR ab-mediated AE, anti-leucine-rich glioma-inactivated-1 (LGI-1) contactin-associated protein-like 2 (CASPR-2) ab-mediated AE, and anti-γ-aminobutyric acid type-B (GABA B) ab-mediated AE [6, 7].
Our case report contains some limitations including the lack of certain clinical and laboratory data such as: medications used for the treatment of depression, the number of oligoclonal bands in the CSF, the method of RT-QuIC detection, and a whole body PET-CT scan (not performed).
In summary, anti-DPPX encephalitis is a rare but increasingly recognised autoimmune condition characterised by a combination of gastrointestinal symptoms, weight loss, and progressive neurological deficits. When evaluating acute/subacute neuropsychiatric symptoms, it is crucial to take into account both prion and immune-mediated disorders in the differential diagnosis, bearing in mind that EEG and 14--3-3 protein levels in CSF are not definitive in distinguishing between these conditions.
To diagnose autoimmune encephalitis and determine the correct treatment, identifying specific antineuronal antibodies in serum or CSF can be highly informative.
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