Changes in DPPX autoantibody levels in autoimmune encephalitis: a case report and brief review

Abstract

Introduction:

Dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis is a recently recognized but rare cause of autoimmune encephalitis. Clinically, it presents with a subacute onset of seizures, cognitive decline, and tremors, often accompanied by gastrointestinal manifestations such as weight loss and vomiting. Temporal fluctuations in DPPX antibody levels have not been previously reported and diagnosing this subtype remains challenging due to its gradual onset, diverse clinical presentation, and possible fluctuations in antibody levels throughout the disease course. Its pathophysiology is incompletely understood, likely involving genetic, environmental, and immune factors.

Case report:

We describe a 22-year-old male presenting with a clinical syndrome consistent with DPPX encephalitis, including seizures, cognitive impairment, and systemic manifestations. Serum testing revealed antibodies to DPPX and voltage-gated potassium channels (VGKC), confirmed by a cell-based assay. The assay was repeated at the initial presentation and was again positive. However, repeat testing several months later, prior to treatment, showed negative cerebrospinal fluid (CSF) and serum DPPX antibodies. Repeat testing on a third occasion also returned negative results. The patient improved significantly after immunotherapy, consistent with an autoimmune encephalitis diagnosis.

Conclusion:

This case highlights the diagnostic challenges of DPPX encephalitis, emphasizing the importance of interpreting encephalopathy panel results within the clinical context. The observed fluctuations in DPPX antibody levels suggest that repeat serum testing may be of utility to reassess diagnosis and guide treatment in clinical cases where there is concern for autoimmune encephalitis.

Introduction

Autoimmune encephalitis (AE) is a rare and complex neurological disorder characterized by inflammation of the brain and caused by the formation of autoantibodies against certain synaptic or membranous neuronal proteins. It is considered one of the most common causes of non-infectious encephalitis [1]. The clinical presentation of AE can be diverse and non-specific to the disease, making diagnosis extremely challenging. It can combine a wide spectrum of cognitive, behavioral, neurological and non-CNS symptoms. The rarity of reported AE cases in the medical literature, combined with its diverse clinical presentations, often leads to delayed or missed diagnoses by clinicians as it requires a high index of suspicion, along with antibody testing and supportive findings from MRI, EEG, and CSF analysis. Diagnosis remains challenging and many cases may remain undiagnosed or even be referred to different specialties as presentations often combine various neurological, gastrointestinal and different systemic disorders, leading to potential delays in recognition and treatment. The variations in clinical presentation are often related to the type of antibodies involved in the disease process, and their targeting of different areas of the nervous system and different neuronal components. For example, while all are associated with potassium channel function, auto-antibodies to gamma-aminobutyric acid A/B (GABA-A/B) receptors lead to seizures, cognitive impairment and respiratory issues; auto-antibodies to contactin-associated-protein-like-2 (CASPR 2) cause limbic issues, peripheral nerve excitability and ataxia, and auto-antibodies to glutamic acid decarboxylase 65 (GAD65) are associated with seizures, memory issues, and stiff person syndrome [2]. Overall, each autoantibody has its unique set of clinical manifestations, which can guide differential diagnosis [3]. Further understanding of all possible presentations of AE can significantly improve patient’s care outcomes and lead to less burden on other clinical specialties, making it easier to make the diagnosis.

The AE disease subtype due to autoantibodies to DPPX, a potassium channel subunit, is primarily characterized by CNS hyperexcitability and gastrointestinal (GI) symptoms including unexplained nausea and diarrhea [4]. It is also associated with weight loss and cognitive symptoms [5]. Less common symptoms of anti-DPPX encephalitis include brainstem or cerebellar disorders, sleep disturbances, and dysautonomia [6]. The various neurological symptoms are likely associated with its widespread distribution in the hippocampus, cerebellum, and striatum, whereas the more restricted expression in the myenteric plexus of the gastrointestinal tract is thought to give rise to the GI features [5].

This case report, to our knowledge, is the first to look at serial changes in DPPX levels over time. Detectable levels of DPPX autoantibodies were inconsistent; suggesting that positive titers for a DPPX associated AE should not be the only diagnostic criteria. If clinical suspicion for an AE is high, it may not only be important to repeat test for autoantibodies over time but also interpret findings in the setting of the clinical context.

Case presentation

A 22-year-old male presented to the hospital for episodes of unresponsiveness lasting minute and which were associated with staring, lip smacking, bilateral hand tapping and hand clenching. His past medical history was significant for asthma and dyslexia but no other chronic medical conditions. Family history was irrelevant except for brain stroke in his maternal uncle. Evaluation at the outside hospital included a comprehensive metabolic profile and cell counts, all normal except for an ALT of 74 and CKs in 280 s. Urine toxicology and urinalysis were negative. The electroencephalogram was normal. MRI brain showed linear areas of T2 hyperintensity in the left thalamus and right cerebellum suggestive of ischemia (Fig. 1). He started on levetiracetam but had a recurrence of episodes over the ensuing months. Repeat MRI of the brain remained unchanged, MRA of head and neck were normal. valproic acid (Depakene) was added, and he was transitioned off levetiracetam to brivatiracetam. Despite these changes, he reported events which would tend to cluster.

Fig. 1.

MRI of brain (sagittal, FLAIR, left) demonstrates a small lacunar area with surrounding T2 FLAIR hyperintensity in the medial aspect of the left thalamus, likely a chronic lacunar infarct. A small focal structural irregularity (coronal, STIR, right) with adjacent prominent sulcus in the right cerebellar lobe, without diffusion or T2 FLAIR hyperintensity and without enhancement, possibly due to a congenital insult or remote ischemic infarct.

He first came to this clinic a year later for a second opinion. The neurological examination was normal, and he was admitted for epilepsy monitoring. Continuous EEG was notable only for right temporal slowing without any spells captured. His anti-seizure medications were changed, and he remained event free for over some 16 months, at which point he began having recurrence of events, now associated with tremors, panic attacks, nausea and vomiting. In retrospect, he had lost 28 pounds over a two-year period. Uptitration of and additions to his anti-seizure medications did not remediate the seizures.

He underwent a reevaluation. Because of the seizures, confusion, and associated nausea and vomiting and weight loss, the serum autoimmune encephalopathy panel (ENS2, Mayo) was sent and notable for anti-DPPX antibodies, in a titer of 1:240 nmol/l. Positive titers were then confirmed by cell-based assay. Repeat cell-based assay was performed and again positive. Neuronal (V-G) K+ Channel Abs were also positive at 0.04 nmol/l (normal under 0.02 nmol/l). Routine EEG showed bifrontal irritability consistent with seizure disorder. Cell counts, electrolytes (sodium 135), liver enzymes, B12, MMA, ANCA, ANA, CRP, TFTs, and SPEP were all normal. MRI of brain with and without contrast showed no new or enhancing lesions. The patient’s presentation aligned with the established diagnostic criteria for autoimmune encephalitis discussed below, demonstrating the subacute onset of symptoms and psychiatric disturbances along with unexplained seizures, labs and MRI findings as well as exclusion of other possible disorders, further reinforced the diagnosis and guided the initiation of immunotherapy.

He was admitted to the hospital given the positive encephalopathy panel. CBC, sodium was 127, HIV 1/2, Lyme, TSH, TTG, DAG peptide, H pylori, SARS COV2, Influenza, RSV, Lipase, hepatitis panel, calprotectin, ammonia, liver enzymes, immunoglobulin levels were all normal. Lumbar puncture was performed but traumatic (WBC 50, RBC 70,856, gluc 68, prot 153). The CSF autoimmune encephalopathy panel (ENC2, Mayo) returned normal. He underwent IVIG treatment five days before.

For that reason, He returned for follow up two months later. Repeat serum autoimmune encephalopathy panel (ENS2, Mayo) was negative for anti-DPPX but positive anti-GAD (titer of 0.08 nmol/l). Despite the new negative serum titers of anti-DPPX antibodies, his presentation was still typical for anti-DPPX encephalitis given his concurrent neurological and GI symptoms along with previous positive titers. The negative serum results generally add to the complexity of the case and warrant a higher index of suspicion to make the diagnosis. However, the 2016 AE clinical criteria emphasize the importance of starting immunotherapy once AE is highly suspected, and infectious etiologies are excluded based on CSF results which were all done. The choice of the initial therapy may be based on clinical evidence and factors related to the patient. After his IVIG treatment improved his symptoms, the patient was then initiated on rituximab therapy, after which he reported a noticeable further improvement in symptoms. Subsequent follow-up evaluations indicated a positive clinical response, supporting the effectiveness of immunotherapy in this case.

Discussion

Autoimmune encephalitis refers to the aberrant production of antibodies against different neuronal surface proteins, causing inflammation of the brain and affecting its functionality. The majority of AE cases have no identifiable cause and the neurological symptoms even for the same AE autoantibodies can be different. The difficulty in ascribing etiology and variations in clinical presentation may extend from the limited panel of autoantibodies, which have been identified and undergo screening. Additionally, the identification of certain antibodies does not exclude the possibility that other, undetected antibodies, might exist. The case presented here further confounds the diagnostic approach as there likely are fluctuations in AE autoantibody levels over time, raising the possible need to perform repeat serial testing, and/or ascribe to other clinical criteria to make a diagnosis.

DPPX function is still not fully understood but it is believed to play an important role in the regulation of synaptic plasticity and neurotransmitter release. The protein is a cell surface regulatory subunit of the voltage-gated A-type Kv4.2 potassium channel, which is expressed in neuronal somata and dendrites where it modulates the frequency of repetitive firing and serves important roles in signal processing [12,13]. It is localized to the hippocampus where it is the predominant Dipeptidyl peptidase like protein in hippocampal pyramidal neurons [11], as well as cerebellum, and myenteric plexus [7,8].

In the gut, it acts as a key component in the generation and propagation of electrical impulses in the GI system. In vitro experiments revealed that patients’ sera and purified IgG increased the excitability and frequency of action potentials in the enteric nervous system neurons which could explain the gastrointestinal symptoms [10].

To date, few cases have been reported on anti DPPX encephalitis and diagnosis remains challenging because of the broad spectrum of possible clinical presentations. It was first described by Boronat et al. in 2013 [4] and is caused by cell surface DPPX autoantigens. Approximately 63 % of affected individuals are males [9]. A previous study done on 4 patients who were suspected to have anti- DPPX encephalitis showed a clinical picture consistent with a syndrome of CNS hyperexcitability including hyperekplexia, myoclonus, tremor, or seizures that in 3 patients were preceded by unexplained weight loss and diarrhea [6]. According to literature review, 53 cases have been reported, of which more than half had prodromal weight loss (52.8 %) and gastrointestinal disorders (58.5 %). Cognitive disorders (74.6 %) and brainstem/spinal cord disorders (75.5 %) were the most common major symptoms (see Table 1 for common presentations). The patient was diagnosed first with a seizure disorder, presented with increased seizure frequency, confusion, along with nausea and vomiting associated with epileptic episodes, and only in retrospect, was weight loss reported.

Table 1.

Common clinical presentations from medical literature for anti-DPPX encephalitis.

Case Number	Symptoms	References
1	Chronic diarrhea, weight loss, CNS hyperexcitability	MSARD Journal [15],
2	Ataxia, Diplopia, mood disturbances	BMJ Neurology Open [16]
3	Cerebellar symptoms: dizziness, unsteady gait	BMC Neurology [17]
4	Neuropsychiatric symptoms: hallucinations, agitation	Cureus [18]
5	Fatigue, confusion, limb soreness, convulsions	Frontiers [19]
6	Altered pain perception, severe weight loss, pruritus	Frontiers [20]
7	Severe gastrointestinal dysmotility with polyneuropathy	JNNP [21]
8	Severe visual and auditory hallucinations	Neuroimmunology Reports [22]
9	Progressive seizures, memory loss, personality changes	Research Square [23]
10	Unexplained startle response, progressive cognitive decline	Frontiers [24]

Specific criteria have been suggested to diagnose AE. Possible AE diagnosis can be made when all three of the following criteria have been met: 1. Subacute onset (rapid progression of <3 months) of working memory deficits (short-term memory loss), altered mental status*, or psychiatric symptoms. 2. At least one of the following: (a) New focal CNS findings, (b) Seizures not explained by a previously known seizure disorder, (c) CSF pleocytosis (white blood cell count of more than five cells per mm³) (c) MRI features suggestive of encephalitis. 3. Reasonable exclusion of alternative causes. Brain MRI is most likely to be normal in early stages of the disease and EEG findings are nonspecific making the diagnosis more challenging. The progression of this disease is often insidious and subacute and varies among different patients [7]. If the patient meets criteria for possible AE, definite AE diagnosis is entertained when autoantibodies are detected. Testing should always be guided by the clinical-anatomical syndrome of the patient to narrow down the scope of investigations. When AE is suspected, CSF analysis is considered the most important evaluation and is usually done as second step after initial lab work and brain MRI. Screening for associated neoplasm may also be done using different modalities such as CT scan and MRI, especially when the patient shows specific symptoms related to a particular cancer. Moreover, serum autoimmune encephalopathy should always be taken to determine the subtype of suspected AE, leading to the diagnosis and appropriate treatment plan. In our case, the patient developed subacute onset of memory/staring episodes and psychiatric symptoms (anxiety), and seizures. Serum labs were initially positive for DPPX but negative on two subsequent occasions, one test which occurred prior to initiation of treatment with steroids and rituximab. His testing, however, also was notable for positive antibodies for VGKC and GAD65, suggesting that other autoantibodies could be contributing to his symptoms. These lab findings challenge the conventional reliance on a single positive or negative test result, demonstrating that negative results do not necessarily exclude an autoimmune etiology. The observed fluctuation in DPPX antibody levels as well as the possible involvement of other antibodies both highlight the need for serial testing to improve diagnostic accuracy and guide treatment options. Recognizing this clinical variability leads to better clinical management strategies, ensuring that patients receive timely and appropriate immunotherapy despite any changes in antibody detectability.

Treatment of AE is mainly based on immunotherapeutic strategies. Intravenous immunoglobulin (IVIG) at a dose of 2 g/kg over 2–5 days is considered a relatively good option for rapid immunomodulation when corticosteroids are contraindicated or when the clinical picture is suggestive of or known to be related to antibody-mediated disease (in our case anti-DPPX encephalitis) [25]. Empiric treatment with intravenous methylprednisolone at a dose of 1 g per day for 3–7 days is also considered a common reasonable approach to achieve initial immunosuppressive and anti-inflammatory effect in AE patients [26] but more preferred in acute or refractory cases. However, for maintenance, second line agents are often used. Both rituximab and cyclophosphamide have been used as second-line agents for rescue therapy in AE with good results [27]. Rituximab is less toxic than cyclophosphamide and therefore is preferentially considered by most clinicians although it may not be as effective for cell-mediated inflammation as in the case of antibodies against intracellular antigens. Finally, screening for AE through paraneoplastic or encephalopathy panels has become increasingly accessible and expansive nowadays. The first study on DPPX associated AE relayed the presence of autoantibodies targeting DPPX in either the serum or cerebrospinal fluid, not necessarily both. Similarly, a previous study reporting DPPX encephalitis detected AQP4 antibodies in the serum (1:375) but not in the CSF [14]. It is unclear whether autoantibody levels fluctuate over time or show differences in the CNS versus serum. The current case emphasizes the temporal challenges when there is suspicion for AE. This patient initially presented with autoantibodies to both VGKC and DPPX in the serum. Within a month and prior to treatment, the CSF encephalopathy panel did not show significant levels of DPPX. Repeat testing several months later was also negative for DPPX but positive for GAD65. The patient improved following immunomodulatory therapy. The results from the encephalopathy panels and the clinical context led to a diagnosis of AE), associated with at least involvement of DPPX autoantibodies (based on Graus et al. criteria).

Conclusion

This case report highlights the challenges accompanying the diagnosis of DPPX AE. The broad spectrum of possible clinical presentations prevents diagnosis based solely on presentation. Routine studies and imaging are often inconclusive. As shown in this report, even the presence of autoantibodies can fluctuate over time so increased awareness among physicians of different possible presentations is essential for early recognition and treatment. In this context, the degree of clinical suspicion based on typical symptoms of AE and the exclusion of other causes through imaging and testing, as well as presence of autoantibodies on testing will be needed collectively to drive diagnosis and treatment. Further research should be done to identify additional biomarkers for improving diagnostic accuracy, optimizing treatment protocols to enhance patient outcomes, and exploring the long-term effects of immunotherapy. This will ultimately guide more personalized therapeutic strategies and improve patient’s outcomes.

Abbreviations:

AE

Autoimmune Encephalitis

DPPX

dipeptidyl-peptidase-like protein 6

MRI

Magnetic Resonance imaging

Availability of data and materials

The datasets generated and/or analyzed during the current case report are not publicly available due to patient privacy but are available from the corresponding author upon reasonable request, pending necessary permissions.