A 75-year-old woman with a history of hypertension and dyslipidemia presented to our hospital with oral and bilateral upper limb tremors that had been worsening over the last 3 months. Her first clinical presentation was intractable oral tremor, which had appeared 8 months prior to her first visit.
At the first visit, she exhibited oral tremor, asymmetric tremor, cogwheel rigidity, brachybasia, postural reflex disorder, and constipation, which were not contradictory to Parkinson's disease (PD). Levodopa/decarboxylase inhibitors were prescribed, which resulted in a slight improvement in her parkinsonism-like syndrome (tremors and rigidities), but not significantly. Two months later, she complained of visual hallucinations. Brain magnetic resonance imaging (MRI) did not show clear abnormal intensities or specific atrophy (Figures 1A-D, M-P). Therefore, we suspect rapidly progressive PD and subsequent dementia with Lewy bodies (DLB), and prescribed donepezil; however, the hallucinations did not improve. The following month, her systemic tremor and visual hallucinations worsened, and irritability increased despite medication use. She was admitted to our hospital for careful examination 3 months after her first visit.
On admission, her vital signs were as follows: body temperature, 37.5 C; heart rate, 80 bpm; and blood pressure, 151/98 mmHg. Her oxygen saturation level was 97% at ambient air.
Neurological examination confirmed disturbance of consciousness (Glasgow Coma Scale score of 13 [E4V4M5]) with severe restlessness, visual hallucination, irritability, cognitive impairment [Hasegawa's Dementia Scale-Revised (HDS-R) score of 6 out of 30], decreased deep tendon reflexes in the lower limbs, severe systemic tremor mainly in the limbs, and asymmetric cog-wheel rigidity in the upper and lower limbs. Due to the irritability and severe tremor, we could not evaluate her neurological symptoms related to ataxia. Moreover, sensory disturbance and limb numbness could not be confirmed. She was unable to stand on admission.
Initial laboratory tests did not reveal any specific abnormalities. Complete blood count, liver function, and renal function test results were assessed to be within reference range (RR) despite the mildly increased C-reactive protein level (2.97 mg/dL; RR: < 0.30 mg/dL). Tumor-specific laboratory tests revealed high serum levels of tumor markers (carcinoembryonic antigen, 6.06 ng/mL; cancer antigen 125, 132.5 ng/mL). The RR of CEA is < 5.0 ng/mL, and CA125 is < 35 ng/mL, respectively. Cerebrospinal fluid analyses showed elevated levels of lactate dehydrogenase (LDH) (42 IU/L; RR: < 25 IU/L) and interleukin-6 (IL-6) (11.3 pg/mL; RR: < 4.0 pg/mL) with normal cell counts (two leucocytes/muL) and total protein levels (43 mg/dL; RR: 10-50 mg/dL). Oligoclonal bands were negative. Serum paraneoplastic screening by fixed TBA did not show any significances (Supplementary Figure 1); however, EUROLINE PNS 12 Ag (Euroimmun) showed a weak positive 6 and 10, suggesting a low titer of anti-AMPH antibodies.
Brain MRI revealed semi-rapidly progressive DCA over a period of 3 months without clear abnormal intensities (Figures 1E-H, Q-T). Contrast-enhanced brain MRI was also performed, but no clear abnormal gadolinium enhancement was observed (data not shown). Contrast-enhanced whole-body computed tomography (CT) did not reveal any tumors, and no epileptic discharges were observed on electroencephalography. A nerve conduction study was not performed before treatment, and radionucleotide testing, such as positron emission tomography-CT, single-photon emission CT, dopamine transporter scan, and 123I-metaiodobenzylguanidine myocardial scintigraphy, could not be performed because it was not available in our hospital.
Based on her symptoms, which did not contradict encephalopathy, and the possible detection of anti-AMPH antibodies, we suspected that she had anti-AMPH syndrome. She received two courses of high-dose methylprednisolone over 2 weeks (1,000 mg/day x 3 days intravenously as one course per week). After treatment, her fever and visual hallucinations resolved completely, and her systemic tremor slightly improved, but remained moderate. At that time, she could stand using an assisting device, but could not walk. However, after initiating intravenous immunoglobulin (IVIg) treatment (4 weeks after the initial high-dose methylprednisolone therapy), she could walk without the use of any assisting devices, and her cognitive impairment partially recovered (HDS-R score of 22). At that time, the abnormal increase in LDH and IL-6 in the cerebrospinal fluid had decreased (LDH, 22 IU/L; IL-6, 2.6 pg/mL). Over the next 5 weeks (9 weeks after initial treatment), her cognitive impairment had almost fully resolved (HDS-R score of 28) and DCA had partially recovered (Figures 1I-L, U-X). To determine the presence of peripheral neuropathy, we performed a nerve conduction study after the IVIg treatment, which showed low-amplitude compound muscle action potential and sensory nerve action potential, suggesting axon loss rather than demyelination (data not shown).
Because the anti-AMPH antibody is known as a paraneoplastic antineuronal antibody, we performed various tests to detect malignancy. Although colonoscopy and random skin biopsy showed normal findings, gastroscopy revealed type 0-IIa gastric tumors, and histological results suggested gastric adenocarcinomas with no evidence of metastasis (Figure 2A). After IVIg treatment (6 weeks after the initial high-dose methylprednisolone therapy), endoscopic submucosal dissection was performed and the tumors were completely removed. The pathological diagnosis was two well-differentiated adenocarcinoma lesions (Figures 2B, C).
Despite active immunotherapy and tumor resection, her oral tremor persisted at a moderate degree. Although, the oral intake of baclofen slightly improved it, she did not experience a full recovery. Nonetheless, she could walk independently without difficulty. The patient was discharged 74 days after admission. We also performed an immunoprecipitation assay since TBA failed to detect anti-AMPH antibodies in the patient's serum. A subsequent western blotting analysis revealed the presence of anti-AMPH antibodies and their continuous decrease 10 months after immunotherapy (Figures 3A-C). The clinical timeline is shown in Supplementary Figure 2.