Rare mixed dementia: A case report

Abstract

BACKGROUND

Autoimmune encephalitis (AE) is a rare and recently described neuroinflammatory disease associated with specific autoantibodies. Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is a rare but treatable type of AE discovered in recent years. Alzheimer’s disease (AD) is a degenerative brain disease and the most common cause of dementia. AD may undergo a series of pathological physiological changes in brain tissue 20 years before the onset of typical symptoms. The stage of mild cognitive impairment (MCI) that occurs during this process, known as MCI due to AD, is the earliest stage with clinical symptoms. MCI is typically categorized into two subtypes: Amnestic MCI (aMCI) and non-aMCI.

CASE SUMMARY

This report describes a patient with rapid cognitive impairment, diagnosed with anti-LGI1 antibody-mediated AE and aMCI, and treated at Peking University Shenzhen Hospital in March 2023. The patient was hospitalized with acute memory decline for more than 3 months. Both the cerebrospinal fluid and serum were positive for anti-LGI1 antibodies, biomarkers of AD coexisting in the patient’s cerebrospinal fluid. Following combination treatment with immunoglobulin therapy and glucocorticoid, plus inhibition of acetylcholinesterase, the patient’s cognitive function significantly improved. Throughout the 3-month follow-up period, a sustained improvement in cognitive function was observed. The results of serum anti-LGI1 antibody were negative.

CONCLUSION

This case has raised awareness of the possible interaction between AE and early AD (including MCI due to AD), and alerted clinicians to the possibility of concurrent rare and common diseases in patients presenting with cognitive impairment.

Key Words: Anti-leucine-rich glioma inactivated 1; Encephalitis; Alzheimer’s disease; Cognitive impairment; Case report

Core Tip: Here we present a case of simultaneous autoimmune encephalitis mediated by anti-leucine-rich glioma inactivated 1 antibody and amnestic mild cognitive impairment caused by Alzheimer’s disease. After active treatment, the patient’s symptoms significantly improved. This case report aims to remind clinical doctors to consider the possibility of rare and common diseases in patients with cognitive impairment.

INTRODUCTION

Autoimmune encephalitis (AE) is a rare and novel autoimmune disease of the nervous system, characterized by autoantibodies targeting the neuronal cell surface or intracellular antigens. A recently identified treatable subtype of AE is anti-leucine-rich glioma inactivated 1 (anti-LGI1) limbic encephalitis, which is induced by LGI1 antibodies[1]. Since their discovery in 2010, LGI1 antibodies have emerged as the second most common cause of encephalitis, following anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis[2,3]. Notable clinical characteristics of this encephalitis include rapidly progressive dementia (RPD), faciobrachial dystonic seizures, refractory hyponatremia, and psychiatric disorders[4-7]. Alzheimer’s disease (AD) is a prevalent neurodegenerative illness characterized by gradual cognitive impairment. Its development can be mainly divided into three stages: Asymptomatic (preclinical AD), predementia [mild cognitive impairment (MCI) due to AD], and dementia (due to AD)[8]. MCI is typically classified into two subtypes, with amnestic MCI (aMCI) characterized by impairments in episodic memory and a higher likelihood of progression to typical AD, while non-amnestic MCI primarily involves deficits in other cognitive functions, such as attention, language, visual-spatial function, or executive function[9]. To our knowledge, the coexistence of rare and common diseases in patients with cognitive impairment is extremely uncommon, with no reports published in China to date[10]. Herein we present the case of a 72-year-old male patient diagnosed with anti-LGI1 antibody-mediated AE and aMCI. The patient exhibited typical features of anti-LGI1 encephalitis with positive anti-LGI1 antibodies detected in both cerebrospinal fluid (CSF) and serum at a titer of 1:100; additionally, AD biomarkers were also present in the patient’s CSF. This case report serves to remind clinicians to consider the possibility of concurrent rare and common diseases in patients presenting with cognitive impairment.

CASE PRESENTATION

Chief complaints

A 72-year-old man sought consultation at the Neurology Department of Peking University Shenzhen Hospital, citing a decline in memory for more than three months.

History of present illness

More than 3 months ago, the patient began to show memory decline, especially recent memory. The patient forgot events that had happened, repeated speech, showed decreased judgment and comprehension, and had decent self-care and emotional management abilities. However, there was intermittent pain and numbness in the scalp, which appeared as a discharge and lasted for several seconds. At the same time, the patient experienced intermittent headaches and scalp numbness, appearing in a discharge pattern that lasted for a few seconds each time. During onset of the disease, the patient sought medical attention at other hospitals, but his symptoms did not improve.

History of past illness

The patient had been examined in another hospital 6 years previously which indicated multiple intracranial lacunar infarctions (specific details unknown), and denied other chronic history.

Personal and family history

The patient’s personal and family history was unremarkable.

Physical examination

On examination, his vital signs were normal with a body temperature of 36.6 °C, pulse rate of 72 bpm, respiratory rate of 20 breaths/minute, and blood pressure of 160/85 mmHg. The findings on auscultation of his heart and lungs were within normal limits. Specialist examination revealed that the patient was alert and articulate, cooperative during the examination, demonstrated a decrease in short-term memory, spatial orientation, judgement, and comprehension abilities. However, his arithmetic skills, ability to perform daily activities, and emotional control remained intact. His bilateral pupils were equal and reactive to light, eye movement was normal, without nystagmus or diplopia. Bilateral nasolabial folds were symmetrical, the tongue was midline, and limb muscle tone was normal. Reflexes were normal, limb strength was 5/5, pathological reflexes were not elicited, bilateral finger-to-nose and heel-knee-shin tests were accurate, superficial and deep sensation were normal, the neck was supple, Brudzinski’s and Kernig’s signs were negative. A positional tremor was observed in the right hand (while writing).

Laboratory examinations

On February 21, 2023, an electroencephalogram (EEG) examination at Weifang Yidu Central Hospital showed borderline findings (alpha waves showed spike-wave trend). On February 28, 2023, the mini mental state examination (MMSE) score was 19 points and the Montreal cognitive assessment (MOCA) score was 17 points recorded at Southern Medical University Shenzhen Hospital. Dynamic video EEG on March 6, 2023, at the same hospital showed normal EEG findings. Inpatient examination did not reveal significant abnormalities. Electrolyte examination on March 13: Sodium (Na): 129 mmol/L and chloride (Cl): 92.7 mmol/L. Re-examination on March 14: Na: 129 mmol/L and Cl: 94.9 mmol/L. Glycosylated hemoglobin was 6.1%; albumin was 32.3 g/L, and albumin/globulin ratio was 1.01. His lipid profile, renal function, homocysteine, coagulation profile + D-Dimer, Vitamin B12 + tumor markers, and preoperative profile did not reveal significant abnormalities. Valproic acid levels (external): Valproic acid (Depakene) was 88.99 g/mL. In apolipoprotein E (ApoE) genotype test (external), ApoE E3/E4 genotype was detected. On March 13, 2023, a lumbar puncture was performed with a lumbar puncture pressure of 85 mmH₂O. CSF examination revealed a total cell count of 91 × 10⁶/L, a white blood cell count of 6 × 10⁶/L, and red blood cell count of 85 × 10⁶/L. Biochemical examination of CSF: Total protein: 351.0 mg/L, glucose: 3.77 mmol/L, and Cl: 112.5 mmol/L. Histopathology showed few lymphocytes. Diagnosis: CSF showed no tumor cells. CSF sent for AD marker tests: Amyloid β-protein (Aβ) 1-40: 18412.44 pg/mL, Aβ1-42: 801.66 pg/mL, total-micro tubule-associated protein (t-tau): 313.44 pg/mL, phosphorylated-micro tubule-associated protein (p-tau): 96.48 pg/mL, and Aβ1-42/Aβ1-40 ratio: 0.04 (Table 1). Serum and CSF sent for AE antibody tests: LGI1 antibody IgG was positive (1:100) (Table 2). Paraneoplastic syndrome antibody testing was negative (Table 2). Long-term video EEG (13 hours) did not reveal any significant abnormalities.

Table 1 Test results of cerebrospinal fluid biomarkers of Alzheimer’s disease.

Tested items	Test method	Results		Reference interval
Aβ1-40	ELISA	18412.44 pg/mL	≥ 7000 pg/mL	Positive
			< 7000 pg/mL	Negative
Aβ1-42	ELISA	801.66 pg/mL	≥ 651 pg/mL	Positive
			551-650 pg/mL	Suspicious
			< 550 pg/mL	Negative
t-tau	ELISA	313.44 pg/mL	≤ 399 pg/mL	Negative
			> 399 pg/mL	Positive
p-tau	ELISA	96.48 pg/mL (increase)	≤ 50 pg/mL	Negative
			> 50 pg/mL	Positive
Aβ1-42/Aβ1-40	ELISA	0.04 (decrease)	> 0.05	Negative
			≤ 0.05	Positive

Aβ: Amyloid β-protein; t-tau: Total-micro tubule-associated protein; p-tau: Phosphorylated-micro tubule-associated protein; ELISA: Enzyme-linked immunosorbent assay.

Table 2 Test results of autoimmune encephalitis-related antibodies.

Tested items	Sample type	Test method	Detection time	Results
Anti-NMDA antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-LGI1 antibody IgG	CSF	CBA	Pre-treatment	1:100 (positive)
Anti-GABAB antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-CASPR2 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-AMPA1 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-AMPA2 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-IgLON5 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-DPPX antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-GlyR1 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-D2R antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-GAD65 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-mGluR5 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-mGluR1 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-Neurexin-3α antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-KLHL11 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-GABAA antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-AQP4 antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-MOG antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-GFAP antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-ganglionic AChR antibody IgG	CSF	CBA	Pre-treatment	Negative
Anti-LGI1 antibody IgG	Serum	CBA	Pre-treatment	1:100 (positive)
Anti-LGI1 antibody IgG	Serum	CBA	Post-treatment	Negative

CSF: Cerebrospinal fluid; CBA: Cell-based assay; NMDA: N-methyl-D-aspartate; LGI1: Leucine-rich glioma inactivated 1; GABAB: γ-amino butyric acid type B; CASPR2: Contactin associated protein 2; AMPA: α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid; IgLON5: Immunoglobulin-like cell adhesion molecule 5; DPPX: Dipeptidyl‐peptidase‐like protein 6; GlyR1: Glycine receptor 1; D2R: Dopamine 2 receptor; GAD65: Glutamic acid decarboxylase65; mGluR5: Metabotropic glutamate receptor 5; mGluR1: Metabotropic glutamate receptor 1; KLHL11: Kelch-like protein 11; GABAA: γ-amino butyric acidtype A; AQP4: Aquaporin 4; MOG: Myelin oligodendrocyte glycoprotein; GFAP: Glial fibrillary acidic protein; AChR: Acetylcholine receptor.

Imaging examinations

On January 18, 2023, the patient consulted at Qingzhou People’s Hospital. Computed tomography (CT) scan + diffuse weighted imaging + cerebral magnetic resonance (MR) angiography + neck MR angiography revealed a cerebral ischemic degenerative infarct, senile brain changes, and atherosclerosis of head and neck arteries. Further clinical correlation was advised.

Imaging examination after admission: Echocardiogram revealed aortic sclerosis with slightly dilated ascending aorta, mild calcification near the mitral annulus with trivial regurgitation, and normal ventricular contraction. Cranial CT + susceptibility-weighted imaging (SWI) + magnetic resonance spectroscopy (MRS) findings were as follows: (1) MRS showed bilateral hippocampal head N-acetylaspartate (NAA) peaks with a decreased NAA/(Choline + Creatine) ratio; (2) Bilateral hippocampal T2-weighted-fluid-attenuated inversion recovery signal was increased, particularly on the left side, suggesting possible hippocampal sclerosis; and (3) Cerebral white matter degeneration was observed at modified Fazekas grade 2 level. SWI indicated a potential venous malformation in the right cerebellar hemisphere (Figure 1).

Figure 1 Magnetic resonance imaging scan of the patient’s brain. A and B: T2-weighted imaging axial image; C and D: T2 fluid attenuated inversion recovery coronal image. It can be seen that the T2 fluid attenuated inversion recovery signal in both hippocampi is increased, with a more significant increase on the left side, indicating that hippocampal sclerosis may be present.

FINAL DIAGNOSIS

The patient’s clinical presentation included a progressive decline in memory of more than 3 months, which is indicative of RPD[11]. After carefully considering the potential causes of RPD, we thoroughly reviewed the patient’s medical history and conducted a battery of additional examinations to exclude possible etiologies. Prior to admission, an external MR imaging (MRI) scan was performed and there was no evidence of cerebrovascular disease, thus ruling out the possibility of vascular dementia. Upon admission, we screened for human immunodeficiency virus, syphilis, tumors, and paraneoplastic syndromes and all results were negative, effectively excluding infection, paraneoplastic syndrome or tumors as likely causes. Importantly, both the patient’s CSF and serum tested positive for anti-LGI1 antibodies while AD markers in the CSF met diagnostic criteria for AD. Based on the patient’s symptoms and signs along with auxiliary examination findings, our final diagnosis was AE mediated by anti-LGI1 antibodies coexisting with AD.

TREATMENT

Therapeutic measures included the following: Steroid (1000 mg for 3 days, then 500 mg for 3 days, then 250 mg for 3 days, then 125 mg for 3 days, and finally 60 mg), intravenous immunoglobulin (IVIg) (0.4 g/kg/day for 5 days), donepezil to improve cognitive function, escitalopram to regulate mood, Na valproate for epilepsy, gastric protection, potassium and Na supplements, appetite stimulants, albumin supplementation, basic cognitive training, and other symptomatic treatments. The patient showed significant improvement in symptoms, stable mood compared to before, and improved speech and logic. The MMSE score before discharge was 27 points, and the MOCA score was 18 points (for elementary education). After discharge, oral steroid administration was continued (reduced by 5 mg every two weeks), and anti-epileptic treatment was recommended.

OUTCOME AND FOLLOW-UP

One month after discharge, the patient's follow-up MMSE score was 24 points and MOCA score was 19 points. Three months after discharge, the serum anti-LGI1 antibody result was negative (Table 2), and the follow-up MMSE score was 26 (Figure 2).

Figure 2 The timeline of relevant results and interventions during the diagnosis and treatment of this patient. MMSE: Mini mental state examination; MOCA: Montreal cognitive assessment; MRI: Magnetic resonance imaging; EEG: Electroencephalogram; CSF: Cerebrospinal fluid; Aβ: Amyloid β-protein; FBDS: Faciobrachial dystonic seizure; Tau: Micro tubule-associated protein; LGI1: Leucine-rich glioma inactivated 1; FLAIR: Fluid-attenuated inversion recovery; HAMA: Hamilton anxiety scale; HAMD: Hamilton depression scale.

DISCUSSION

The patient was primarily admitted with RPD, and combined with the age of onset in this patient, neurodegenerative disease was first considered, possibility AD. A previous report of a patient admitted with cognitive impairment, initially considered as AD, was eventually proved to be anti-LGI1 encephalitis[12]. Therefore, in addition to considering the possibility of AD, we also evaluated the possibility of encephalitis. We noted significant hyponatremia in this patient and the presence of involuntary tremors (which we eventually attributed to classic facial-arms bradykinesia) during hospitalization and epileptic seizures diagnosed by an external hospital. In addition to cognitive impairment, these symptoms meet the criteria for anti-LGI1 encephalitis[5-7]. The tests for AE-related antibodies resulted in a positive anti-LGI1 antibody test (with both blood and CSF anti-LGI1 IgG antibody titers being 1:100). In addition, an MRI scan suggested the possibility of hippocampal sclerosis, confirming our diagnosis based on the diagnostic criteria for AE[13,14].

Neurodegenerative diseases such as AD cannot be ignored as the patient ages[15]. The test results for Aβ and tau AD markers (Aβ1-42/Aβ1-40 decreased, p-tau increased) meeting the diagnostic criteria for AD[16] and are considered to be MCI due to AD. Combined with the patient’s cognitive impairment, this was ultimately attributed to aMCI. To our knowledge, this is the first reported case of a patient diagnosed with both anti-LGI1 encephalitis and aMCI. The primary treatment for LGI1 encephalitis is immunotherapy, which includes steroids and immunoglobulins[17]. For AD, acetylcholinesterase inhibitors have been proven to be beneficial for mild to severe AD[18]. For patients with prodromal AD (including MCI due to AD), donepezil is considered effective[19]. Therefore, our patient received high-dose methylprednisolone combined with IVIg immunotherapy and acetylcholinesterase inhibitor treatment (donepezil). The patient’s initial MMSE score of 19 and MOCA score of 12 at admission improved to an MMSE score of 27 and MOCA score of 18 at discharge. Three months after discharge, serum anti-LGI1 antibody level was negative, and the follow-up MMSE score was 26 points. The treatment was successful, highlighting the importance of an early definitive diagnosis to improve patient prognosis.

AD is a continuous disease spectrum, including the pre-clinical stage of AD, MCI due to AD, mild AD, moderate AD, and severe AD[20]. Reports documenting the coexistence of AE and AD are scarce, and ours is the inaugural report of concurrent anti-LGI1 encephalitis and aMCI. It has been postulated that the neuropathological alterations typical of early-stage AD may already be present at the initiation of AE. The ongoing inflammatory processes could potentially worsen such changes, or alternatively, the symptomatic manifestations and progression of AD might be driven by damage associated with AE[21].

The current mechanisms of AE combined with AD are not fully understood. Some studies have found that patients with AE can often exhibit dementia-like symptoms. In a national cohort study assessing the cognitive characteristics of middle-aged and elderly patients with anti-LGI1, anti-NMDAR, anti-γ-amino butyric acid type B receptor, and anti-contactin associated protein 2 encephalitis, encephalitis with anti-LGI1 antibody was the most prevalent subtype in this age group, with clinical manifestations often mimicking dementia[22]. It is generally believed that the pathogenesis of dementia, particularly AD, is associated with autoimmunity, including classical autoantibodies and functional autoantibodies[23]. Some studies have found that the CSF concentration of progranulin (PGRN) may serve as a biomarker for acute NMDAR-AE, while high levels of t-tau may indicate a risk of hippocampal sclerosis. Both PGRN and t-tau are biomarkers of neurodegenerative diseases, suggesting that the pathological processes of AE and AD may influence each other[24-26].

As the sensitivity of detection technology improves, the coexistence of AE and AD is becoming increasingly prevalent, but the potential connection between them remains unclear. Some researchers now believe that inflammation related to AE could accelerate the accumulation of tau neuropathology in susceptible individuals and could be associated with hippocampal atrophy and persistent cognitive diseases like AD[27].

In the case of LGI1 encephalitis, LGI1 protein is most prominently expressed in the hippocampus and temporal lobe cortex[2,4], and LGI1 encephalitis is most likely to occur in elderly individuals[28,29]. When autoimmune inflammatory activity occurs, it may induce neuropathological changes in the hippocampus, leading to early AD changes. Overall, we believe there may be a link between the neurological damage induced by AE and the pathological changes of early AD (including MCI due to AD), which warrants further research.

CONCLUSION

Once the cause of cognitive impairment is determined, subsequent treatments can be established. Therefore, an early and accurate diagnosis is essential for improving patient prognosis. With the advancement of biomarker detection technology, the detection rate of rare diseases such as anti-LGI1 encephalitis will increase. In the future, the overlap of rare and common diseases might become more frequent. The primary goal of this case report is to suggest that when encountering patients with rapidly progressive cognitive impairment, we should consider the possibility of rare diseases like AE coexisting with common diseases such as AD. This approach will help to achieve early diagnosis and treatment, thereby improving patient prognosis as much as possible.