Multiple system atrophy mimics CASPR2 antibody-associated disease: a case report

Abstract

Aim: Multiple system atrophy (MSA) and CASPR2 antibody-associated disease bear their own characteristics.

Case presentation: A 58-year-old woman presented with a 26 months history of uncoordinated gait and slurred speech. Her serum was positive for anti-CASPR2 antibodies, and MRI revealed atrophy of the brainstem and cerebellum. She underwent three plasma exchanges (PE) and received high doses of corticosteroids without any apparent effect. Her autonomic dysfunction improved after repetitive transcranial magnetic stimulation. Eventually, a diagnosis of MSA-cerebellar phenotype(MSA-C) was made.

Conclusion: With increased availability of tools for neuron antibody detection, physicians need to be aware of the possibility that antibodies may accompany other diseases. This report underscores the modern dilemmas caused by available and extensive neuron antibody testing.

Plain Language Summary

There is a certain degree of difficulty in diagnosis of MSA, especially in the early stage and it is easy to be confused with degenerative diseases such as PD. With a thoroughly study of autoimmune diseases of the nervous system, it was found that the clinical symptoms of CASPR2-associated disease overlapped with MSA. In this report, a 58-year-old woman was reported to have uncoordinated gait and slurred speech, and anti-CASPR2 antibodies were found in the blood and cerebrospinal fluid for multiple times, which brought great challenges to the diagnosis. After immunotherapy, anti-CASPR2 antibodies titers declined, but the clinical symptoms and brainstem and cerebellar atrophy were exacerbated, MSA-C was finally diagnosed and rTMS treatment seems helpful.

Plain language summary

Article highlights.

• MSA is hard to be distinguished clinically from other disorders, particularly in early stages. Pathological biopsy is difficult to perform, which is decisive for diagnosis.

• MRI ‘hot cross bun’ sign and ‘putaminal rim’ sign have a certain specificity for MAS of diagnosis, with specificity of 97% and 90%, respectively.

• CASPR2 antibody-associated disease has seven core symptoms, namely cerebral symptoms, cerebellar symptoms, peripheral nerve hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain and weight loss. And some of its symptoms are similar to those of MSA.

• We firstly reported a patient with potential MSA-C who exhibits symptoms of cerebellar ataxia, parkinsonism, insomnia, weight loss, frequent upper lid twitch, poor response to levodopa, anti-CASPR2 antibodies in the serum and pons and cerebellum atrophy.

• The patient of the current report was used to be misdiagnosed as anti-CASPR2 encephalitis and received immunotherapy, the anti-CASPR2 antibodies titers declined, but the clinical symptoms and brainstem and cerebellar atrophy were exacerbated.

• Anti-CASPR2 antibodies are rarely seen among MSA patients. If dystonia and autonomic symptoms patients with anti-CASPR2 antibodies, follow-up MRI is required, to confirm the presence of brainstem and cerebellar atrophy to avoid missed diagnosis.

• Anti-CASPR2 antibodies are not always pathogenic antibodies, while the IgG titer is lower than 1:200.

1. Introduction

Multiple system atrophy (MSA) is a rare, sporadic, adult-onset neurodegenerative disorder that is clinically characterized by a combination of parkinsonism, cerebellar ataxia and autonomic dysfunction [1]. It is consisted of two subtypes, which are MSA-parkinsonian phenotype (MSA-P) featured by parkinsonism, and MSA-cerebellar phenotype (MSA-C) featured by cerebellar dysregulation, respectively. Given its variable clinical presentations, MSA is hard to be distinguished clinically from other disorders, such as Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration, particularly in its early stages. Patients with cerebellar phenotype of MSA may mimic other adult-onset ataxias due to alcohol consumption, chemotherapeutic agents, toluene inhalation, vitamin E deficiency and paraneoplastic, autoimmune or genetic ataxias [1].

Neuropathological studies suggest that a large number of glial cells in the central nervous system contained α-syn-positive inclusions, and there were degenerative changes in the structure of the striatal substantia nigra or olivine pontine cerebellum, which can only be found after the patient has passed. As a result, a large number of studies have been devoted to the search for biomarkers and imaging tests to diagnose and predict MSA [2,3]. Extracellular vesicles can reflect neuronal status and biochemical processes in brain tissue [4], and seed amplification assays may be helpful in detecting the amount of α-syn in serum and cerebrospinal fluid (CSF) extracellular vesicles [5]. However, the detection rate of α-syn in patients with MSA varies widely from <10 to 35%. Besides, no elevation of α-syn in blood and CSF has been reported in MSA cases. Atrophy of the putamen, pons, midbrain and cerebellum are the main structural feature of MSA, and the well-known ‘hot cross bun’ sign and ‘putaminal rim’ sign can be seen on T2-weighted imaging, with specificity of 97 and 90%, respectively, but limited sensitivity of 50% and 75%, respectively. In addition, new magnetic resonance technologies such as diffusion-weighted imaging and magnetization transfer imaging have been studied, and only region-of-interest (ROI) volumetric analyses are able to reflect the global brain atrophy rate of MSA patients [3], but due to insufficient observation time and limited number of included cases, this conclusion needs to be verified by further experiments. Seed amplification assays are becoming widely accepted and highlighted for the diagnosis of MSA, while extracellular vesicles prove to be unreliable. Neuroimaging is still in progress.

CASPR2 antibody-associated disease was previously thought to be associated with limbic encephalitis, acquired neuromyotonia and Morvan syndrome. However, recently it is found that its spectrum of clinical symptoms is growing to include cerebellar symptoms, autonomic dysfunction, insomnia and weight loss [6]. Cerebellar ataxia was found in 14.7% of the patients with anti-CASPR2 antibodies [7]. Compared with CASPR2 disease, MSA has a relatively slower onset and progression, while autoimmune encephalitis has an acute or subacute onset and a rapid progression; hence, MSA is rarely misdiagnosed as autoimmune encephalitis. Herein, we are the first to report a patient with potential MSA-C who exhibits symptoms of cerebellar ataxia, parkinsonism, insomnia, weight loss, frequent upper lid twitch and anti-CASPR2 antibodies in the serum. The patient was previously diagnosed with autoimmune disease (CASPR2 antibody-associated).

2. Case presentation

2.1. Patient information

A 58-year-old with her BMI was 31.11 kg/m², was hospitalized in the Neurology Department of our medical center. She complained of limb weakness, uncoordinated gait and slurred speech. Her symptoms insidiously began 26 months ago and had a chronic progression. In the most severe situations, she was unable to grab a tablespoon with her hands while cooking and could not walk up a flight of stairs. She had severe insomnia (sleeping for only 2 hours) and a weight loss of 6 kg (within 2 months) but failed to seek medical attention. Twenty-four months ago, her gait imbalance degraded so much that she was unable to walk even with assistance from her family. She had slurred speech, nocturia (>2 episodes per night), slowing mobility and rapid eye movement sleep behavior disorder (RBD) when dreaming. Brain MRI diagnostic report indicated that she was normal, but cerebellar atrophy was found on both MRI T2 and “the vertical signs” of the brainstem when we retrospectively analyzed her MRI scans (Figure 1A). She took traditional Chinese medicine decoction orally, but showed no positive effect. Eleven months ago, she exhibited symptom of frequent upper lip twitching and was hospitalized in the neurology department of another hospital. During this hospitalization, anti-CASPR2 antibodies were found in a concentration of 1:10 in her serum but not in her CSF by a cell-based assay (CBA, Supplementary S1). Neurotrophic therapy with vitamin supplement ceased the upper lip twitching. However, her other symptoms remained the same. Eight months ago, her anti-CASPR2 antibody titers increased to a serum concentration of 1:100 by both CBA and tissue-based assay (TBA, Supplementary S1). Brain MRI diagnostic report did not show any trouble but cerebellar atrophy was noticed on MRI T2 and ‘the vertical signs’ of the brainstem when the MRI scans (Figure 1B) were retrospectively analyzed. She was diagnosed with ant-CASPR2 encephalitis and treated with 1 g intravenous methylprednisolone (IVMP) for 5 days followed by 1 mg/kg oral prednisolone and 3 plasma exchange interventions. Thereafter, her weight loss ceased, and her sleep disorder improved by a small margin. Seven months ago, serum anti-CASPR2 antibody titers decreased to a concentration of 1:32, but her symptoms remained unchanged. She reported no family history of ataxia.

Figure 1.

MRI progressing and disease evolution of the case. (A) T2WI showed a slight “vertical line sign” (arrow) and mild atrophy of right cerebellar hemisphere (asterisk). (B) T2WI showed slightly worsened “vertical line sign” (arrow) and atrophy of right cerebellar hemisphere (asterisk) compared with Figure 1A. (C) T2WI showed the hot cross bun sign of pons (rectangle) and the atrophy of the right cerebellar hemisphere (asterisk) that were seen more severely than on previous MRI. (D) T2WI showed the putamen was normal (arrowhead). (E) the course of the person's disease development and treatment.

2.2. Clinical findings

In neurological examination, several findings were made including dysarthria, reduced facial expressivity, slightly increased muscle tone in the left upper extremity and right leg, bilateral upper extremity hyperreflexia, dysmetria on finger-nose tests and heel-knee-shin tests and wide-based gait and impaired tandem gait. The Mini-Mental State Examination score was 27 and that of Montreal Cognitive Assessment test was 19, which did not support the diagnosis of dementia with Lewy bodies and corticobasal degeneration. Besides, a Hamilton Depression Scale and Hamilton Anxiety Scale scores revealed moderate symptoms of depression and anxiety. In addition, the 0.25 g levodopa impact test was negative, which excluded the diagnosis of Parkinson's disease. The blood pressure changes were lower than 30 mmHg while standing, seated, or in supine position.

2.3. Diagnostic assessment

We firstly reexamined anti-CASPR2 antibody level by TBA (Supplementary S1), and then reexamined them once again with CBA (Supplementary S1), whose results revealed titers of 1:50 and 1:10, respectively, in the serum and negative titers in the CSF. CSF cell count, protein, sugar, chlorine, staining and immune index detection were all normal, however the neuronal antigen was negative. MRI revealed hot cross bun sign of pons and cerebellar atrophy (Figure 1C) and the putamen was normal (Figure 1D). Nerve conduction study and electromyography indicated that the right peroneal nerve was not elicited, and sympathetic skin responses of the bilateral legs were abnormal, but peripheral hyperexcitability was absent. Transcranial Doppler assessment indicated that the left substantia nigra in the midbrain and the regions of the left lenticular nucleus had a certain degree of hyperechogenicity. We also tested her paratumor antibodies, blood tumor markers, thyroid ultrasound, abdominal ultrasound, urinary ultrasound, superficial lymph node ultrasound and chest CT, but no tumor or tumor related antibodies were found. There was no evidence of other autoimmune diseases, and the absence of peripheral hyperexcitability.

2.4. Therapeutic intervention & follow-up

The patient was diagnosed as potentially having MSA-C. She was treated with symptomatic therapy and underwent rTMS twice daily for 5 days. During the follow-up, she reported the disappearance of nocturia (3 months' follow-up). What's more, the other symptoms still existed after starting the rTMS treatment; and she complained of increased walking instability and needed to be supported (8 months’ follow-up). MRI showed atrophy of olive, pontine and cerebellum (Figure 1E).

3. Discussion

To our knowledge, this is the first MSA-C case presenting with anti-CASPR2 antibodies in the serum, which used to be misdiagnosed as autoimmune encephalitis. In this case, the patient exhibited symptoms of autonomic disorder rapidly progressing parkinsonism, cerebellar syndromes, unexplained urinary frequency and poor response to levodopa. Atrophy was observed on an MRI scan of the pons and cerebellum which met the possible MSA-C diagnostic criteria. The patient also had symptoms of transient upper lip twitching, RBD and no “not supporting”, i.e., no “pill-rolling” rest tremor. Therefore, a diagnosis of possible MSA-C was made according to the consensus guidelines [1].

However, the patient also had anti-CASPR2 antibodies in her serum, which may confound existing diagnosis. CASPR2, a cell adhesion protein of the neurexin family, was expressed in the central and peripheral nervous systems, including the cortex, basal ganglia, substantia nigra, limbic circuitry, brainstem and cerebellum. The anti-CASPR2 antibodies may lead to neurological autoimmune diseases in the form of CASPR2 associated disease. This disease is more common among male population and often occurs at ≥50 years of age. It has seven core symptoms, namely cerebral symptoms, cerebellar symptoms, peripheral nerve hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain and weight loss [6]. Detection of antibodies in the CSF or serum is of significant diagnostic value, as it possibly relates to mainly peripheral antibody production. The study indicated that the serum antibody positive of the patients was 100%, and her CSF positive was 56% [8]. It was proposed that the CSF positive patients mainly showed marginal encephalitis without neuromyotonia or Morvan syndrome, while the simple seropositivity patients mainly showed neuromyotonia or Morvan syndrome [9]. So antibodies in the serum have a higher diagnostic sensitivity. The age of the patient, positive serum antibody, and several other core symptoms, made her previously be misdiagnosed as CASPR2-associated disease. But the patient demonstrated no clear neuromyotonia or Morvan syndrome. Besides, the anti-CASPR2 antibodies were found positive in 7.8% of the patients with relapsing-remitting multiple sclerosis. However, antibodies were not found to be associated with disease subtype or prognosis at 5-year follow-up [10]. Meanwhile, only one in three patients of CASPR2 associated disease shows temporal lobes with high T2 signal intensity, hippocampal atrophy and medial temporal lobe or hippocampus sclerosis on brain MRI scans [11]. In addition, only 4 patients of CASPR2-associated disease have been reported to have mild cerebellar atrophy on their brain MRI scans [12,13]. Almost all patients of CASPR2-associated disease have benefited from immunotherapy, and their MRI lesions significantly recovered [11]. But the clinical symptoms and MRI lesions of the patient of the current report did not improve following immunotherapy. Her antibody titers declined, but her brainstem and cerebellar atrophy were exacerbated, and there has not been any report on patients with pons or brainstem atrophy [12,13]. Therefore, some scholars had proposed that anti-CASPR2 antibodies are not always pathogenic antibodies, while higher serum antibody titers and MRI lesions have more accurate diagnostic value for diseases and an IgG titer of 1:200 was the best upfront cut-off and the low-titer antibody is a nonspecific result of another immune process [8]. In addition, substantial evidences indicate a causal relationship between anti-CASPR2 antibodies and Parkinsonism, and autonomic dysfunction has only been documented in a few instances [6]. Since other alternative causes cannot be reasonably excluded in the case of the patient of the current report, the CASPR2 associated disease was excluded in accordance with the diagnostic criteria for Graus autoimmune encephalitis [14].

RBD is usually used to predicts neurodegeneration in synucleinopathy, such as MSA. However, increasing evidence has shown that RBD is also found in some non-synucleinopathy diseases, including CASPR2 associated disease [15], and may be related to CASPR2 in brainstem. While anti-CASPR2 associated RBD is often much responsive to immunotherapy, our patient did not improve. On the contrary, their RBD and nocturia improved following rTMS. Non-invasive rTMS is a safe technique that selectively modulates the excitability of neuronal populations and their connected neural networks via a current induced by an electromagnetic field. Although the rTM mechanism still remains unknown, it is increasingly applied in MSA. Many studies have demonstrated that rTMS may improve cerebello-frontal connectivity, balance functions [16], motor symptoms and functional connectivity involving the default mode, cerebellar and limbic networks, which may be related to the fact that rTMS increases activation in the primary motor area and cerebellum. These positive functional connectivity changes have been exhibited by fMRI but have not been found to be linked to RBD and nocturia. Although several studies indicate that transcutaneous tibial nerve stimulation may improve urgency, nocturia and other urinary dysfunction in PD patients, rTMS-related studies have not reported any supporting evidence. The urinary dysfunction present in all MSA patients may be related to the abnormalities in coordination between the bladder, urinary sphincter and the pontine storage center, which lies ventrolateral to the pontine micturition center, hypothalamus, cerebellum, basal ganglia and frontal cortex [17]. As such, we speculated that the RBD and nocturia improvement following rTMS might be related to rTMS changes in functional connectivity involving brainstem and cerebellum, which supported a diagnosis of MSA.

Characteristic MSA brain MRI signal intensity abnormalities include the “hot cross bun” sign which is of high positive predictive value for the diagnosis of MSA, and the vertical line appeared earlier than the horizontal line [18]. In the first and second MRI scans, our patient presented a gradual appearance of the vertical line, while her third MRI scan showed a “hot cross bun,” which was consistent with those previously reported patterns. The “hot cross bun” sign can be witnessed in other disorders, too, including corticobasal degeneration, hereditary cerebellar ataxia, probable dementia with Lewy bodies, to name just a few [19]. However, our patient had no obvious cognitive disorders or family history of ataxia, thus lending no strong support to the presence of these diseases. So far, no definitive examination methods for MSA has been found except for an autopsy-based pathological diagnosis.

4. Conclusion

Anti-CASPR2 antibodies are rarely seen among MSA patients. Our case suggests that there is a coincidence between symptomatology and antibody. When the titer of antibody is less than 1:200, the correlation between clinical symptoms and MRI findings and antibodies should be examined in great detail, and the value of antibodies be carefully evaluated.

5. Future perspective

The patient and her son are very grateful for our attention to her condition, and they hope that our reporting will help more patients, and get the attention of other scholars to such patients and they will ultimately benefit from it.

Funding Statement

The language polish and layout fee of this study was supported by the National Natural Science Foundation of China (grant number: 82271503 and 82071461).

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17582024.2024.2388506

Financial disclosure

The language polish and layout fee of this study was supported by the National Natural Science Foundation of China (grant number: 82271503 and 82071461). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval (Medical Ethics Committee of Shaanxi Provincial People's Hospital for the research described (SPPH-LLBG-17-3.2) and/or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.