Parkinsonian Syndrome with Frontal Lobe Involvement and Anti-Glycine Receptor Antibodies.

Parkinson’s disease is characterized by rigidity, tremor, shuffling gait, and other symptoms, such as loss of smell [1]. Atypical Parkinsonian syndromes include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multisystem atrophy.

Different PSP phenotypes include classic Richardson’s syndrome, PSP-Parkinson’s syndrome, PSP-corticobasal syndromes, PSP-speech language syndrome, PSP with predominant cerebellar ataxia, and PSP with frontal presentation [2]. Richardson’s syndrome is characterized by mostly symmetrical, axially accentuated, akinetic-rigid Parkinson’s syndrome, as well as a vertical supranuclear gaze paresis, early falls, and a poor response to levodopa [2,3]. PSP with frontal presentation is rare, often showing the symptomatology of a behavioral variant of frontotemporal dementia years before the motor features of PSP become evident [2,4]. The pathological hallmarks are microtubule-associated tau proteins in neurofibrillary tangles (so-called 4-repeat tauopathy), oligodendrocyte coils, and astrocytic tufts [5]. Magnetic resonance imaging (MRI) characteristically shows atrophy in the midbrain and superior cerebellar peduncles, while [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG PET) displays hypometabolism of the frontal cortex, caudate, midbrain and thalamus [2], of which the midbrain findings have been incorporated in the novel diagnostic criteria as a supporting imaging finding [5]. Dopamine transporter (DAT) imaging [e.g., [¹²³I]FPCIT single-photon computed tomography (FPCIT SPECT)] demonstrates severely and fairly symmetrically reduced nigrostriatal innervation [6]; cerebrospinal fluid (CSF) tau/p-tau levels are normal or even lower than those of controls [2]. PSP has a poor prognosis because no causal or sustained effective symptomatic treatment is currently available [2,3].

The four most important CBD subtypes are probable corticobasal syndrome (CBS), frontal behavioral-spatial syndrome, nonfluent/agrammatic variant of primary progressive aphasia, and PSP syndrome [7]. CBS is characterized by asymmetric akinetic-rigid Parkinsonism, limb dystonia or limb myoclonus, and other cortical symptoms, such as ideomotor apraxia or alien limb phenomena [8]. Like PSP, CBD is also a 4-repeat tauopathy [9]. MRI can show asymmetric frontoparietal atrophy in the course of the disease; the brain stem MRI findings are typically inconspicuous [3]. FPCIT SPECT reveals asymmetric reduction of the presynaptic dopamine transporter density, and FDG PET displays usually markedly asymmetrically reduced frontoparietal glucose metabolism [6,10,11]. There is also no known causal treatment [8].

Secondary forms of movement disorders may occur in the context of autoimmune encephalitis with different antineuronal antibodies [12,13,14,15]. Dyskinesias are found in anti-NMDA-receptor (R) encephalitis. Cerebellar ataxia is associated with a number of paraneoplastic, antineuronal antibodies against intracellular antigens. PSP phenotypes are described for anti-Ma2 and anti-IgLON5 antibodies, Stiff-Person spectrum diseases are associated with anti-GAD5 antibodies or anti-glycine receptor (anti-GlyR) antibodies, and progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome is associated with anti-GlyR antibodies [13,16].

Patients with anti-GlyR antibody syndrome are, on average, 50 years old and suffer from spasms, stiffness, rigidity, myoclonus, and related walking difficulties (with falls in 80%). Limb paresis and pyramidal signs are observed in 60% of cases, trigeminal, facial, and bulbar disturbance or excessive startle reflexes in 57%, and oculomotor disturbances with nerve or gaze palsy in 53%; cognitive impairment is present in half of patients [17]. A recent publication has pointed to an extension of the spectrum with several visual symptoms, including visual hallucinations, synesthesia and intermittent diplopia [18]. Subacute courses occur in 44% of cases, while a primary chronic course has been described in 11% [17]. Tumor association is observed in <5% [16]. MRI of the brain reveals pathological findings in 28% of patients, and spinal lesions in 22%. Electroencephalography (EEG) pathologies have been found in 71%, with slowing in about half (52%) [17]. CSF abnormalities are observed in about half of the cases [19], with increased white blood cell (WBC) counts in most (43%) [17]. Intrathecal anti-GlyR antibody synthesis was observed in the majority of cases [17,20,21]. The response to anti-inflammatory treatment is mostly good, with the modified Rankin scale scores dropping from a median of 5 during disease peak to 1 [17].

Overlaps between neurodegenerative and immunological mechanisms have been previously described in anti-IgLON5 disease [22,23]. In anti-IgLON5 encephalopathy, antibodies against the neuronal cell-adhesion protein IgLON5 have been shown to be associated with tauopathy of the brainstem tegmentum [22].

Rationale: The symptoms of Parkinsonian syndromes with frontal lobe involvement, such as PSP or CBD, and autoimmune anti-GlyR antibody syndrome have obvious overlaps. From a clinical perspective, the distinction between the two is important because of the different therapy options and prognoses indicated. New developments in the field also raise the question of the interaction between neurodegenerative and immunological diseases. The case presented here shows a patient in this conflicting area, with Parkinsonsian syndrome with frontal lobe involvement and anti-GlyR antibodies.

The female patient was 63 years old when presented to our hospital. She has given her signed written informed consent for this case report, including all the data and the presented images, to be published. At that time, she suffered mainly from personality changes (reduced energy, social withdrawal, introversion, emotional flattening, avoidance of eye contact, loss of interest in discussions, lack of insight), cognitive deficits (attention/concentration and working memory deficits), and Parkinson’s syndrome with left-emphasized bradykinesia/reduced amplitude in finger tapping, hypomimia, bilateral rigor, and a postural instability with a tendency to fall (Hoehn and Yahr stage IIb).

Up to the age of 60, the patient had always been mentally healthy, in a good mood, and active. At the age of approximately 60 years, she developed growing insomnia (with problems in maintaining sleep and early awakening). At the age of 61, a change in her behavior became increasingly apparent. Her energy levels were reduced, she withdrew socially, seemed affectively flattened, and experienced more insecurity and anxiety. In addition, the patient developed delusional fears (felt spied on and therefore wanted the roller shutters closed continuously). Consequently, depression with psychotic symptoms was diagnosed. Muscle tone was assessed as normal at that time. However, retrospectively, a reduced facial expression had already been observed by her husband. The sleep disturbances improved with low-dose mirtazapine (3.75 mg/day). Treatment with duloxetine (60 mg/day) led to slight improvement of delusional fears. In the further course, an increasing personality change was observed. The patient was less happy, more introverted, appeared to be increasingly emotionless, and was no longer able to maintain eye contact. The MRI examination of the brain and the EEG remained inconspicuous (at the age of 61 years). In CSF diagnostics, identical oligoclonal bands (OCBs) in CSF and serum were found, indicating a systemic process. The neurodegeneration markers (tau, p-Tau, β-amyloid quotient, 14-3-3) were in the normal range. At the same time, she developed increasing trunk stiffness and left accentuated rigor. At the age of 62, elevated anti-GlyR IgG serum–antibodies with a titer of 1:640 (reference: <1:20; Laboratory Krone, Bad-Salzuflen, Germany) were found, and a left-accentuated Parkinson’s syndrome became more and more apparent. Anti-inflammatory treatment with prednisolone (3 × 1000 mg/day) was started and repeated five times every 4 weeks. Tolerability was good, but no relevant clinical improvement was observed. The antibody titers only changed by one titer step (to 1:320). Thus, maintenance therapy with azathioprine (150 mg) was started. On this therapeutic regimen, a stabilization of the symptoms could be achieved, but no sufficient improvement. The antibody titers dropped to 1:80 (reference: <1:20). Additional levodopa treatment (with only 187.5 mg/day) was well tolerated, and led to the slight improvement of mood and rigor (see Figure 1).

Following admission to our specialized ward at the age of 63, three years after the onset of the neuropsychiatric syndrome, a comprehensive clinical examination was performed. The MRI of the brain revealed low-grade mesencephalon atrophy, but there was no clear “hummingbird sign”. Other brain regions, including the basal ganglia and limbic system, were unremarkable (Figure 2). The MRI of the spinal cord showed no evidence of myelopathy or contrast-enhancing lesions. In the visual assessment and independent component analyses, the EEG was normal. The CSF revealed slightly increased protein concentration. The anti-GlyR serum IgG antibody titers were 1:80 (reference: <1:20; Laboratory Krone, Bad-Salzuflen, Germany), and the CSF testing was negative (identical OCBs in serum and CSF were no longer positive). Tau, p-tau and β-amyloid quotients were in the normal range. In addition, slightly elevated anti-thyroid peroxidase (TPO) antibodies were found in the serum (Table 1). The FDG PET depicted a moderate bilateral hypometabolism of the frontal lobes, the midbrain, and, to a lesser extent, the caudate nuclei as well, compatible with a frontotemporal lobar degeneration (Figure 3). On the whole body FDG PET/CT, there was no indication of a neoplastic process. For examination of nigrostriatal degeneration, which in severe expression would be more typical for PSP than FTD, an FPCIT SPECT was performed, which revealed a severely reduced dopamine transporter availability in both striates, indicating pronounced nigrostriatal degeneration (Figure 3). Thus, nuclear medicine findings are well compatible with PSP [5,6,11], whereas the lack of asymmetry argues against CBD [6,10,11]. In the neuropsychological testing of attention performance (TAP), a clear impairment of both basal and more complex attention functions was detected. The “Consortium to Establish a Registry for Alzheimer’s Disease” (CERAD) test battery revealed deficits in verbal memory and executive performance (word fluency, set-shifting; Figure 4).

Her history was negative for in-utero/birth complications, febrile convulsions, inflammatory brain diseases, severe systemic infections, or craniocerebral traumata. She had no history of a neurodevelopmental or personality disorder. She never had a tumor disease but suffered from Hashimoto’s thyroiditis supplemented with l-thyroxin (75 µg/ day). Her father died early of a heart attack. Parents, grandparents, and siblings are not aware of any neurological, autoimmune or tumor diseases.

This case study is of a female patient exhibiting a remarkable neuropsychiatric syndrome, beginning with insomnia and followed by increasing frontal lobe-linked personality changes. These changes initially mimicked depression with psychotic symptoms, and the patient later developed severe cognitive deficits and left-side accentuated Parkinson’s syndrome with postural instability.

In the absence of oculomotor abnormalities, the presence of a frontal syndrome and mild postural instability leads diagnosis towards a “suggestive frontal PSP” [5]. The (only) minimal improvement with levodopa and the tendency to fall would also be compatible with PSP [3]. A supranuclear palsy of the eye was not currently present, but this symptom can occur after a delay [2]. Alternatively, the clinical diagnosis could be probable CBD, with frontal behavioral-spatial syndrome and asymmetrical Parkinsonism [7]. The nuclear medicine findings, which showed hypometabolism of the frontal lobes, midbrain and caudate nucleus on FDG PET, as well as strongly reduced dopamine transporter availability in both striates on FPCIT SPECT, are well in line with PSP [5,6], whereas the lack of asymmetry in both examinations argues against CBD [6,10,11]. There was a low-grade midbrain atrophy, which did not decisively argue for or against one of the two 4-repeat tauopathies [5,25,26]. In summary, the patient appeared to be suffering from a Parkinsonian syndrome with prominent frontal lobe involvement, but a definitive PSP or CBD diagnosis could not be made. This is in line with the notion that the 4-repeat tauopathies PSP and CBD may be considered to represent different manifestations of a disease spectrum with several common clinical, neuroimaging, pathological, genetic and biochemical features, which prohibits accurate in vivo distinction between both diseases [11,27].

The elevated anti-GlyR antibodies (with a maximum titer of 1:640) suggested a possible autoimmune cause for the complex Parkinsonian syndrome with frontal lobe involvement. Initial positive identical OCBs in serum and CSF indicate a systematic process. The perinuclear signal in many neurons (likely reflecting ANAs) in the tissue-based assays could be indicative of increased autoimmune susceptibility. Anti-GlyR antibodies are typically associated with Stiff-Person spectrum syndromes or PERM, but they can also be syndromally associated with a very “colorful picture” of symptoms [17,21,28]. The presence of anti-GlyR antibodies in other neuro-immunological diseases, and in the “colorful clinical picture”, mitigates their high specificity, although these antibodies can be pathophysiologically relevant if they reach the brain [29]. The coexistence of Parkinsonian syndrome with frontal lobe involvement and anti-GlyR antibodies may relate to at least three possible causes and consequences:

This paper describes a neuropsychiatric syndrome that initially manifested with purely psychiatric symptoms, and later developed into a Parkinsonian syndrome with frontal lobe involvement, likely caused by a 4-repeat tauopathy (PSP or CBD). A primary causal role of the additionally detected anti-GlyR antibodies was unlikely. However, the anti-GlyR antibodies might have developed secondarily to neurodegeneration, without overt clinical effects. Therefore, such antibodies might have the potential to modify the clinical course of classical movement disorders. Further research is needed on the role of immunological processes in neurodegenerative diseases like Parkinsonian syndromes.

DE was funded by the Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg.

R.W., K.D. and L.T.v.E. treated the patient. D.E. performed the data research and wrote the paper. S.M. supported the data search and created Figure 1. H.P. and M.R. performed the neurological interpretation. H.P. performed the CSF tissue tests. T.S. performed the neuropsychological testing and interpretation. P.T.M. performed the nuclear medicine investigations and interpretation. P.T.M. critically revised the paper. H.U. performed and interpreted the MRIs. K.N., K.R., K.D. and L.T.v.E. supported the clinical and laboratory interpretation. All authors were critically involved in the theoretical discussion and composition of the manuscript. All authors have read and agreed to the published version of the manuscript.

The article processing charge was funded by the German Research Foundation (DFG) and the University of Freiburg in the funding program Open Access Publishing.

DE: None. HP: None. MR: None. TS: None. RW: None. KN: None. SM: None. KR: None. HU: HU is shareholder of the Veobrain GmbH. KD: Steering Committee Neurosciences, Janssen. PTM: Advisory boards and lectures within the last three years: GE, Philips, OPASCA, Curium, Desitin and Medac. LTvE: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen and Cyberonics.