A Unique Case and Presentation of Anti-GAD Paraneoplastic Encephalitis

Case Description

We report a case of 52-year-old man who initially presented with aggressive, erratic behavior. The patient was last seen two days prior to the index visit by neighbors. During a wellness check on the day of his presentation, the patient was found confused and altered. When the Emergency Medical Services (EMS) arrived at the scene, the patient was reportedly covered in feces and blood, with abrasive injuries on face and bilateral upper and lower extremities. The patient was agitated and striking his head against the wall. The Advanced Life Support (ALS) team administered 2 mg of IM Ativan for agitation after discussion with local medical control. The patient did not respond to initial treatment and an additional 100 mg of IM ketamine was administered, after which agitation improved. EMS continued transportation to the Emergency Department (ED). On arrival, the patient was noted by the clinical team to be unresponsive to painful stimuli. The patient was emergently intubated for airway protection.

Patient’s medical history included pancreatitis, degenerative disk disease, PTSD, chronic lower back pain, and a diagnosis of “COVID encephalopathy,” three months prior. At that time, the patient was found unresponsive and brought to an outside hospital, where he was intubated for airway protection. While it is unclear what his immediate mental status preceding this event was, three months prior to this event, the patient had multiple visits for back pain. During these visits, it was documented repeatedly that the patient was fully oriented to person, place, and time, and able to give detailed history and participate in physical exam. In the initial work-up, there were no acute central nervous system findings on computed tomography (CT) or MRI imaging identified. He did, however, test positive for COVID, with CSF analysis showing elevated protein of 121 mg/dL, 0 WBC count, 55 mg/dL glucose, and elevated serum GAD65 antibody level at 0.19 nmol/L. The patient received remdesivir, dexamethasone, and IVIG for COVID encephalopathy at an outside hospital, then was transferred to this current facility for plasmapheresis. Following treatments, patient was subsequently extubated, downgraded to general medicine floor, and eventually discharged. At the time of discharge, patient was again noted to be fully oriented, with normal cognition and speech, and was without any documented signs of abnormal or bizarre behavior. Patient was also ambulatory at this time using a rolling walker.

During the initial work-up in the ED during the index visit, the patient was found to have a leukocytosis of 30.8 K/uL, with a neutrophil percentage of 93.90%. A critical CT image of the chest, abdomen, and pelvis with intravenous contrast was obtained. It revealed an acute-appearing thrombus in proximal aortic arch not seen on CT imaging from two months prior (Figure 1), centrilobular emphysema with apical bulla, and a lesion in the upper pole of the left kidney suggestive of possible renal neoplasm. CT imaging of the head revealed a previously known left frontal gliosis (Figure 2). Due to concern for meningitis vs encephalitis, lumbar puncture was performed. The CSF analysis during this visit showed 1 WBC, 59 mg/dL of protein, and 90 mg/dL of glucose. Repeat Mayo CSF autoimmune encephalopathy panel revealed elevated serum GAD54 Ab assay level of 0.06 nmol/L. Patient was treated with moxifloxacin, vancomycin, and acyclovir, then subsequently admitted to the Intensive Care Unit from the ED.

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Figure 1.

CT Imaging Showing Acute-Appearing Thrombus in Proximal Aortic Arch

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Figure 2.

CT Imaging of Head Without Contrast Showing Left Frontal Gliosis

At the time of admission, patient was started on levetiracetam with a loading dose of 2g. While in the ICU, video EEG revealed no seizure activity but did show focal slowing and epileptiform discharges independently over the bilateral temporal regions, left greater than right, suggestive of independent areas of focal cerebral dysfunction and with epileptogenic potential. This EEG finding raised concern for multiple pathologies including viral encephalitis, embolism with seizure foci, and paraneoplastic syndrome. MRI Brain without contrast revealed T2/FLAIR hyperintense signal distributed within periventricular and subcortical white matter tracts most compatible with mild white matter microangiopathic ischemic change (Figure 3), and no acute infarction. Due to insufficient sample after lumbar puncture, no viral panel was obtained to evaluate for HSV. The neurologist, in conjunction with the infectious disease team, agreed that there was lower suspicion for HSV encephalitis and thus decided not to repeat the lumbar puncture. The cerebrospinal fluid cell count showed only 1 white blood cell at this time, which was highly inconsistent with a viral process. 10 mg/kg acyclovir q8h was given for two days but was discontinued on Day 3 due to low suspicion.

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Figure 3.

MRI Brain Without Contrast Showing Mild White Matter Microangiopathic Ischemic Change, No Acute Infarction

Subsequent renal MRI confirmed renal cell carcinoma (Figure 4), which raised even greater suspicion for paraneoplastic encephalitis. The patient was treated with a total of 5-days of steroid therapy with methylprednisolone 500 mg BID, as well as continued regimen of levetiracetam 750 mg BID. Five days after his initial arrival at the ED, patient was extubated successfully, but still noted to be slightly confused per the primary team despite being awake and alert. The exact quality of this confusion is unknown as no specific description of this confusion was documented. Patient continued to have similar mental status on the following day. At this point, the decision was made by the critical care team in conjunction with neurologist to begin plasmapheresis. On the day following the first session of plasmapheresis, the same critical care provider who had noticed the confusion documented improvement in the patient’s mental status. Plasmapheresis treatment was comprised of five total sessions over six days. Session #1 involved 1.0 Plasma Volume with 100% replacement using 5% albumin. Sessions #2-4 involved 1.0 Plasma Volume with 50% replacement using 5% albumin and 50% replacement using FFP. Final session #5 involved 1.0 Plasma volume replaced 100% using 5% albumin. Towards the end of his hospitalization, patient became alert and oriented to person and approximate date though vague as to location. He followed commands appropriately, and was able to ambulate using a rolling walker. Patient was discharged to home with a rolling walker after 16 days of hospitalization.

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Figure 4.

MRI Showing Renal Cell Carcinoma

Discussion

Paraneoplastic encephalitis (PE) is a neurologic syndrome that is associated with one or more antibodies produced during an immune response against cancer. ¹ Despite this association, antibodies may not be documented in cases of PE. ² Common antibodies associated with PE include anti-MA, anti-Hu, anti-CRMP5, anti-CV2. While there have been reported associations of anti-GAD in PE, these are exceedingly rare. Even among these reported cases, a quarter of these have been linked to thymoma or small cell lung cancer.^3,4 In the setting of renal cell cancer, although paraneoplastic syndromes may occur up to 10%–40% of patients, the majority of these syndromes involve hypercalcemia, or constitutional symptoms, such as fever or weight loss, malaise, hypertension, endocrine abnormalities, or polycythemia.^5-7 In a study looking at three patients with renal cell cancer that did show signs of limbic encephalitis (demonstrating altered mental status, memory impairment, or seizure), the autoantibodies in these cases included microsome antibody or weakly positive ANA. ⁸ While the complexity of this patient’s clinical course and the lack of definitive criteria for anti-GAD PE make this a difficult diagnosis, this patient represents the first reported potential case in the setting of renal cell carcinoma to the author’s knowledge.

GAD is an enzyme that functions to decarboxylate glutamate to gamma-aminobutyric acid (GABA). As such GAD antibodies have been associated with clinical features considered to result from reduced GABA-ergic transmission.^9,10 In a patient with suspected or known carcinoma presenting with erratic behavior, altered mental status, agitation, or neurologic deficits, anti-GAD paraneoplastic encephalitis should be included in the provider’s differential. Presenting symptoms can be very diverse. In one previously documented case of anti-GAD encephalitis, the patient presented with seizures, and behavioral disturbances, ranging from aggression and hallucinations to dysautonomia. ¹¹ Although difficult to know whether it was present in our patient due to sedation by EMS and prompt intubation and on arrival to the emergency department, there have also been reported cases of patients with anti-GAD antibody-positive patients presenting with stiff person syndrome. ¹²

While exclusion of alternative diagnoses and presence of anti-GAD antibody in this patient’s CSF supports a diagnosis of anti-GAD encephalitis, this diagnosis is difficult to make based solely on the presence of anti-GAD antibody. The specificity of anti-GAD antibody in serum for this diagnosis is lacking, with limited direct associations between anti-GAD antibody and neurologic disease. More information may be gleaned from the comparative ratios of anti-Gad antibody in serum to CSF in the setting of neurologic syndromes; however, this analysis is limited. In part, this is due to overlap with other autoimmune pathologies such as DM1. Further studies are needed to determine if there is a means to use anti-GAD antibody levels to diagnose and predict immunomodulator-responsive encephalitis. Furthermore, given the limited specificity or ability of this antibody to predict immunomodulating therapy response, clinicians are advised to use the presence of this antibody as one data point among many to guide clinical judgment on tp iniaite immunomodulators.^13,14

Work-up for PE should consist of imaging studies and CSF analysis including autoimmune panel and EEG, as well as the infectious, hematologic, and metabolic work-up. Imaging studies contribute heavily to the diagnosis of paraneoplastic encephalitis. MRI studies in particular have been known to provide useful information when it comes to identifying cases of PE. The usual MRI findings in PE involve abnormalities in the temporal lobes. ¹⁵ However, there are fairly high rates of negative MRI findings. MRI studies of our patient showed T2/FLAIR hyperintense signals most compatible with mild white matter microangiopathic ischemic change rather than large confluent lesions, thus unlikely to be responsible for the extent of altered mental status and abnormal behavior found in our patient. ¹⁶ If no known history of cancer, screening for malignancies may also be included in the work-up reasonable to include in the work-up.^1,17 Early consultations to services such as neurology and oncology will facilitate diagnosis and treatment process.

Traditional treatment approaches include steroids, immunosuppression, plasma exchange, and IVIG. The latter has previously been shown to improve neurological functional outcomes in autoimmune encephalitis. ¹⁸ In one study, IVIG was shown to be an effective and safe treatment for stiff person syndrome in patients with anti-GAD antibodies. ¹⁹ Given the similar repeated episode altered mental status three months later from the index visit, it is very possible that the patient’s condition improved after the IVIG and plasmapheresis that treated the encephalitis rather than COVID. The decreased GAD antibody level from the first hospitalization may also be from the IVIG therapy. When known, treatment of the underlying malignancy can also have a positive influence on the recovery process. One study exploring paraneoplastic syndrome in renal cell cancer patients found that there was resolution of paraneoplastic syndrome after nephrectomy in 52.1% of patients. ²⁰ Our patient received a total of 5 plasmapheresis as well as steroid treatments as part of the therapeutic course.

Anti-GAD encephalitis has been associated with a constellation of symptoms including seizures, psychosis, ataxia, and personality changes.^3,21 In our case, the patient presented with compatible symptoms including agitation, altered mental status, and erratic behavior with EEG showing epileptic foci. The presence of anti-GAD antibodies on initial CSF analysis combined with subsequent results inconsistent with viral illness (<5 WBCs) are consistent with anti-GAD PE. ¹⁷ Exclusion of other diagnoses based on laboratory studies, CSF analysis, MRI imaging, and EEG lend support to the suspected diagnosis of anti-GAD encephalitis. Given the epileptic foci seen in the initial EEG, there was also a question as to whether seizure disorder was a potential etiology of patient’s altered mental status, especially as an anti-epileptic medication was co-administered during this hospital course. Even so, there are several features that lead away from this diagnosis. Firstly, our patient who had no known prior history of seizures was initially found covered in feces and striking his head against the wall, which is highly atypical of a seizure or sequela of seizure disorder. Secondly, despite multiple days of treatments with anti-epileptic medication, patient was still confused to the day following his extubation. This confusion improved immediately on the day following his first plasmapheresis session, which would not have been effective should the primary source of the altered mental status been seizure disorder. Furthermore, as mentioned above, seizures are known to occur with anti-GAD encephalitis, thus the presence of seizures cannot exclude the diagnosis of PE.

Conclusion

In cases of neuropsychiatric symptoms with known renal cell carcinoma, anti-GAD-associated paraneoplastic encephalitis should be considered as a part of the differential. Studies including but not limited to MRI of the brain, lumbar puncture with CSF analysis for presence of antibodies, and EEG should be conducted to guide diagnosis. In suspected anti-GAD-associated paraneoplastic encephalitis, treatments may include steroids, immunosuppression, plasma exchange, and IVIG, as well as treatment of the underlying offending pathology. To the authors’ knowledge, this patient represents the first reported case of a potential anti-GAD-associated paraneoplastic encephalitis associated with renal cell carcinoma.