You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


1. Introduction {#sec1}
===============

Autoimmune encephalitis (AE) is a clinically challenging diagnosis usually suspected in cases of altered mental status or seizures after excluding other more common diagnoses. (Anderson 2008) Common presenting signs are nonspecific-memory impairment, hallucinations, anxiety, irritability, depression, seizures, or sleep alterations \[[@B1], [@B2]\]. These symptoms may develop over a course of weeks to months. AE may be of infectious, paraneoplastic, or immune-mediated etiology. Differential diagnoses, diagnostic approaches, and clinical criteria for diagnosis of paraneoplastic AE have been proposed previously \[[@B3]--[@B5]\]. Most recently, consensus on diagnostic criteria for autoimmune encephalitis has been published \[[@B6]\]. Positive serology with specific antibodies and negative workup for malignancy are important in the diagnosis \[[@B6]\]. With emerging evidence of reversibility of AE with immunotherapy, early diagnosis is important and should not be delayed while awaiting for serological data \[[@B6]\]. Thus, early neuroimaging, along with the initial neurological assessment, plays an important role \[[@B6], [@B7]\].

Voltage-gated potassium channel (VGKC) and N-methyl-D-aspartate (NMDA) antibodies are increasingly being recognized as associations of AE due to easy availability of serological testing. Since the presenting symptoms are nonspecific, establishing neuroimaging correlates to guide diagnostic workup may allow for timely therapeutic interventions. We present seven patients (six positive for VGKC and one positive for NMDA antibodies) with AE highlighting the importance of early neuroimaging with brain magnetic resonance imaging (MRI) and \[^18^F\]-fluoro-deoxy-glucose positron emission tomography (FDG-PET).

2. Methods {#sec2}
==========

We screened medical records of patients evaluated at a tertiary academic medical center between 2004 and 2010 billed under ICD-9 codes 276.1 and 323.9. A retrospective review of 848 case records with clinical diagnosis of AE and/or limbic encephalitis upon presentation was done. Of these, 102 patients had paraneoplastic panel results available with 7 being positive (6 positive for VGK and 1 positive for NMDA antibodies). All panels were processed by Mayo Medical Laboratories (Rochester, MN). The cases were further reviewed for historical information, diagnostic workup, medications administered, and neuroimaging findings. The Institutional Review Board approved the study protocol.

3. Results {#sec3}
==========

Patient characteristics are described in [Table 1](#tab1){ref-type="table"}. Mean age was 56.7 years (range: 22 to 91 years of age; 4 males and 3 females). All presented with the chief complaint of altered mental status and/or seizure. One patient had elevated microsomal antibodies (138.6 IU/mL; normal \< 5 IU/mL) and thyroglobulin antibodies (1209 IU/mL; normal \< 10 IU/mL) with a normal thyroid stimulating hormone (TSH) (4.63 *μ*U/mL) and free T4 (1.4 *μ*U/mL) in addition to VGKC antibody. None of the patients had diabetes. Computed tomography (CT) of chest, abdomen, and pelvis was negative in all patients. CSF was significant in three patients with elevation of white cell count in two patients and mild elevation of protein in a third patient.

The mean time of symptom onset to positive antibody serology was 102.1 days (range: 8 to 185 days; [Table 1](#tab1){ref-type="table"}). The average VGKC titer on initial presentation was 1.44 nmol/L (normal \< 0.03) \[[@B8]\]. NMDA titer was not resulted. All but one patient received intravenous methylprednisolone, intravenous immunoglobulin, and plasmapheresis in various combinations. Four of the six treated patients improved with treatment with minimal residual cognitive deficits. One patient did not receive treatment and improved remarkably prior to discharge and returned to her baseline health five months after presentation. One patient expired from an unrelated medical cause. One patient progressed to persistent vegetative state. At least three patients had serial serology titers for the antibodies. Only one case made significant improvement in titer level following treatment. Six of the seven patients required prolonged antiepileptic agents for seizure control.

The average time between symptom onset and first neuroimaging modality was 48.6 days (range: 4 to 184 days). MRI of the brain was the first modality in four cases ([Table 2](#tab2){ref-type="table"}). CT of head was performed first in the other cases. The average time from onset of symptoms to first positive finding on neuroimaging (i.e., T2/fluid attenuated inversion recovery (FLAIR) hyperintensity on MRI or FDG-PET hypermetabolism) was 80.0 days (range: 16 to 184 days). Four patients had mesial temporal lobe hyperintensity on T2/FLAIR weighted MRI. One patient with VGKC AE had T2/FLAIR weighted hyperintensity of the restiform bodies. The other patient with VGKC AE had global atrophy. The patient with positive NMDA AE had serial MRIs that were all unremarkable except development of generalized atrophy ([Table 3](#tab3){ref-type="table"}).

FDG-PET scans were available in six of the patients. All six patients had hypermetabolism of mesial temporal structures ([Table 3](#tab3){ref-type="table"}). In three of these cases, the FDG-PET was positive (i.e., mesial temporal lobe hypermetabolism) before any changes were visualized on brain MRI. Serial MRI scans in two of the patients subsequently became positive for mesial temporal lobe hyperintensity 1 and 72 days following the FDG-PET scans. These patients were positive for VGKC. The brain MRI for the patient positive for NMDA AE only showed generalized atrophy on subsequent imaging. [Figure 1](#fig1){ref-type="fig"} is an illustrative example of FDG-PET findings prior to MRI findings. CT of head was unremarkable for any acute process in all the presented cases.

4. Discussion {#sec4}
=============

This case series of VGKC and NMDA autoimmune encephalitis illustrates the importance of neuroimaging with emphasis of early FDG-PET particularly in cases of initial nondiagnostic MRIs. It also demonstrates the extralimbic nature that may occur with VGKC antibody positive AE.

It is accepted that paraneoplastic and nonparaneoplastic antibodies can present at distant sites from the limbic system, but they usually do so in addition to limbic involvement \[[@B9]\]. The importance of the solitary finding in this case is not clear. VGKC receptors are known to be found in the peripheral nervous and autonomic nervous systems in addition to the central nervous system. Recent studies have illustrated that antibodies directed to proteins (e.g., contactin-associated protein-like 2 (CASPR2) and leucine-rich glioma-inactivated protein 1 (LGI1)) within the VGKC complex or to Kv1 channels may explain why patients present with such varied clinical and radiological presentations \[[@B8], [@B10], [@B11]\]. The diversity in neurologic phenotypes seems to be independent of the VGKC antibody titer level \[[@B8]\]. Even at low levels of positive VGKC, the finding of LGI1 and/or CASPR2 antibodies can result in a diverse spectrum of neurologic phenotypes \[[@B8]\]. Nevertheless, LGI1 antibodies typically result in higher titers of VKGC antibody titers, and LGI1 antibodies will typically have cortical (e.g., seizures and/or altered mental status) presentations \[[@B8]\]. These subtypes of VGKC antibody can be found in patients with extralimbic presentations \[[@B8]\]. This suggests a critical evaluation of extralimbic regions of the brain for MRI changes in patients with suspicion for AE. Importantly, VGKC positivity in the absence of antibodies to either LGI1 or CASPR2 does not seem to be clinically relevant as a marker of autoimmune inflammation \[[@B11]\]. Unfortunately, our seropositive-VGKC patients had serum samples tested prior to the accepted reporting of the subtypes of the VGKC macromolecule complex.

Why VGKC antibodies caused mostly limbic hyperintensity on MRI and the NMDA antibodies did not is not entirely known. It has been suggested that the restricted diffusion seen on the diffusion weighted images (DWI) is due to the presence of abundant number of inflammatory cells along with increased amounts of interstitial water which accounts for the relative normal apparent diffusion coefficient (ADC) images \[[@B12]\]. The hyperintensity is typically asymmetric and rarely enhances with contrast \[[@B13]\]. VGKC are also among the earliest ion channels to appear during brain development. It is not clear whether limbic involvement represents concentration of VGKC in these patients implying a pathogenetic role of the VGKC antibodies or presence of antibodies is an incidental finding. Importantly, the hyperintensity on MRI can persist over months to years and may actually lead to progressive mesial temporal sclerosis \[[@B14]\].

Another important finding in this case series is the lag time in developing noticeable changes on MRI. Two cases showed mesial temporal lobe hypermetabolism on FDG-PET prior to changes on brain MRI. Additionally, the patient with NMDA AE showed mesial temporal lobe hypermetabolism without MRI findings. The utility of FDG-PET in the diagnosis and monitoring of autoimmune encephalitis has been shown to be significant \[[@B15]--[@B17]\]. FDG-PET of the brain typically shows hypermetabolism in similar regions as the brain MRI hyperintensity \[[@B9]\]. The described findings on brain MRI have included T2/FLAIR hyperintensities in the mesial temporal lobes (either unilateral or bilateral) that rarely enhance, generalized atrophy, or corpus callosum or basal ganglia hyperintensities \[[@B3], [@B18]\]. Thus, it is recommended that FDG-PET be obtained early in diagnostic workup of suspected cases of autoimmune encephalitis, especially when the initial MRI of the brain is unremarkable.

In conclusion, FDG-PET is a useful tool in the diagnostic workup of autoimmune encephalitis, such as in patients with VGKC or NMDA receptor antibodies. FDG-PET can be positive despite an unremarkable brain MRI. Additionally, maintaining awareness of extralimbic hyperintensity on MRI is also recommended.

The authors would like to thank Welf Saupe of the eResearch Center at the Cleveland Clinic for his assistance in identifying patients for the research project.

Disclosure
==========

S. Hantus has served as a consultant and on advisory boards for UCB pharma.

Competing Interests
===================

The authors declare that they have no competing interests.

Authors\' Contributions
=======================

C. R. Newey, A. Sarwal, and S. Hantus contributed equally to the writing of the case and formatting the images. C. R. Newey and A. Sarwal have no financial disclosures to report.

![Neuroimaging of VGKC antibody. The initial, unremarkable axial T2/FLAIR MRI of the brain (a) followed by FDG-PET showing significant asymmetric hypermetabolism of the bilateral mesial temporal lobes (arrows; (b)) with repeat axial T2/FLAIR demonstrating hyperintensity in bilateral mesial temporal lobes (arrows; (c)) that significantly improved by the last T2/FLAIR (d).](AD2016-9450452.001){#fig1}

###### 

Patient characteristics.

  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Patient      Sex   Age (years)   Clinical features                                                                                            Cancer   Antibody monitoring (days)   VGKC titers (nmol/L)   NMDA serology   Symptom onset to diagnosis (days)   CSF WBC (cells/mm^3^)   CSF protein (mg/dL)   Treatment                                                             Max number of AEDs
  ------------ ----- ------------- ------------------------------------------------------------------------------------------------------------ -------- ---------------------------- ---------------------- --------------- ----------------------------------- ----------------------- --------------------- --------------------------------------------------------------------- --------------------
  1            F     91            Altered mental status                                                                                        No       Initial                      0.13                   NA              8                                   3                       57                    None                                                                  None

                                                                                                                                                                                                                                                                                                                                                                                     

  2            M     59            Autonomic seizure                                                                                            No       Initial\                     1.58\                  NA              94                                  1                       40                    IVMP × 5 days, PLEX × 5 days                                          3
                                                                                                                                                         54\                          4.22\                                                                                                                                                                                          
                                                                                                                                                         161\                         15.8\                                                                                                                                                                                          
                                                                                                                                                         273                          1.94                                                                                                                                                                                           

                                                                                                                                                                                                                                                                                                                                                                                     

  3            F     52            Altered mental status, depression                                                                            No       Initial                      0.13                   NA              178                                 NA                      69                    IVMP × 5 days, IVIG × 5 days                                          2

                                                                                                                                                                                                                                                                                                                                                                                     

  4            F     35            Flu-like symptoms, complex partial seizure, hyponatremia, elevated microsomal and thyroglobulin antibodies   No       Initial\                     2.8\                   NA              54                                  2                       34                    IVIG × 3 days, IVMP × 3 days, PLEX × 5 days                           5
                                                                                                                                                          24                          0.77                                                                                                                                                                                           

                                                                                                                                                                                                                                                                                                                                                                                     

  5            M     54            Altered mental status, hyponatremia, gelastic seizure                                                        No       Initial                      3.89                   NA              185                                 12                      47                    IVMP × 5 days, PLEX × 5 days                                          4

                                                                                                                                                                                                                                                                                                                                                                                     

  6            M     84            Altered mental status, hyponatremia, tonic seizure                                                           No       Initial                      0.13                   NA              177                                 2                       48                    IVMP × 5 days, PLEX × 3 days/week for 2 weeks                         2

                                                                                                                                                                                                                                                                                                                                                                                     

  7            M     22            Psychosis                                                                                                    No       Initial\                     NA                     Positive\       19                                  64                      23                    IVMP × 5, PLEX × 10 d, IVIG × 5, cyclophosphamide, prednisone 5 qd    5 
                                                                                                                                                         56                                                  Positive                                                                                                                                                                

                                                                                                                                                                                                                                                                                                                                                                                     

  *Average:*         *56.7*                                                                                                                              *51.6*                       *3.5*                                  *102.1*                             *12.0*                  *45.4*                                                                                       
  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

VGKC, voltage-gated potassium channel antibody; CSF, cerebrospinal fluid; IVMP, 1 gram of intravenous methylprednisolone; IVIG = 0.4 g/kg/d of intravenous immunoglobulin; PLEX, plasma exchange; F, female; M, male; NA, not applicable.

###### 

Structural and physiological workup.

  Patient     Days from onset to first image   First image modality   Days from onset to first positive image finding   First positive image modality   Days from onset to first EEG   Days from onset to first positive EEG findings   EEG finding
  ----------- -------------------------------- ---------------------- ------------------------------------------------- ------------------------------- ------------------------------ ------------------------------------------------ ------------------------------
  1           4                                CT                     NA                                                NA                              159                            NA                                               Normal
  2           46                               MRI                    109                                               PET                             46                             81                                               Vertex seizure
  3           73                               MRI                    120                                               PET                             83                             180                                              Periodic pattern
  4           184                              MRI                    184                                               MRI                             183                            183                                              Nonlocalizable status
  5           10                               MRI                    18                                                MRI                             53                             NA                                               Generalized slowing
  6           14                               CT                     16                                                MRI                             22                             22                                               Right frontotemporal seizure
  7           9                                CT                     33                                                PET                             14                             18                                               Bifrontal seizure
                                                                                                                                                                                                                                        
  *Average*   *48.6*                                                  *80.0*                                                                            *80.0*                         *96.8*                                           

EEG, electroencephalogram; CT, computed tomography; PET, positron emission tomography; NA, not applicable.

###### 

MRI and PET findings.

  Patient   MRI brain findings                                                                                      PET findings
  --------- ------------------------------------------------------------------------------------------------------- -------------------------------------------
  1         Global atrophy out of proportion to patient\'s age                                                      NA
  2         Bilateral mesial temporal lobe hyperintensity on T2/FLAIR without contrast enhancement                  Left mesial temporal lobe hypermetabolism
  3         Bilateral hyperintensity on T2/FLAIR in the restiform bodies bilaterally without contrast enhancement   Right temporal lobe hypermetabolism
  4         Left unilateral mesial temporal lobe hyperintensity on T2/FLAIR without contrast enhancement            Left temporal lobe hypermetabolism
  5         Right unilateral mesial temporal lobe hyperintensity on T2/FLAIR without contrast enhancement           Bilateral temporal lobe hypermetabolism
  6         Right unilateral mesial temporal lobe hyperintensity on T2/FLAIR without contrast enhancement           Bilateral temporal lobe hypermetabolism
  7         Unremarkable brain                                                                                      Bilateral temporal lobe hypermetabolism

[^1]: Academic Editor: Corrado Betterle