Frontotemporal Dementia Misdiagnosed for Post-Treatment Lyme Disease Syndrome or vice versa? A Treviso Dementia (TREDEM) Registry Case Report

Abstract

We describe the case of a 61-year-old woman diagnosed with Borreliosis at the age of 57. Subsequently, the patient developed depression, anxiety, and behavioral disturbances. A lumbar puncture excluded the condition of Neuroborreliosis. The diagnostic workup included: an MRI scan, a ¹⁸F-FDG PET, a ¹²³I-ioflupane-SPECT, an amyloid-β PET, a specific genetic analysis, and a neuropsychological evaluation. Based on our investigation, the patient was diagnosed with probable behavioral-frontotemporal dementia (bvFTD), whereas in the previous years, the patient had been considered firstly as a case of Post-Treatment-Lyme Disease and, secondly, a psychiatric patient. We believe that, in the present case, such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing as a contributory cause.

Keywords

Borrelia depression frontotemporal dementia Lyme disease misdiagnosis post-treatment Lyme disease

INTRODUCTION

Frontotemporal lobar degeneration (FTLD) encompasses a group of clinical disorders associated with the degeneration of frontal and/or anterior temporal lobes [1]. Such conditions may result from heterogeneous pathological processes and may be related to different genetic backgrounds.

The behavioral variant of frontotemporal dementia (bvFTD) is typically characterized by progressive changes in: personality, behavior, insight, judgment, reasoning or language abilities, with relative preservation of the episodic memory [2]. Given the wide range of symptoms, bvFTD often entails the need to consider a differential diagnosis with other neurodegenerative diseases and psychiatric disorders. The consequent considerable heterogeneity in clinical presentation may be responsible for a high proportion of misdiagnoses that, in the context of psychiatric diseases, can rise up to 50%. Notwithstanding this considerable heterogeneity, there is current evidence that the use of metabolic imaging with ¹⁸F-FDG-PET can improve the diagnostic accuracy [3].

Cognitive and behavioral symptoms may occur, albeit with a prevalence not fully known, after a Borrelia infection, configuring the framework of the so-called post-treatment Lyme disease syndrome (PTLDS). PTLDS is defined by the persistence of symptoms such as fatigue, arthralgia, myalgia, cognitive dysfunction, or radicular pain for over six months following a documented clinical and laboratory evidence of previous infection with B. burgdorferi and after a completed course of appropriate antibiotic therapy, when other somatic or psychiatric causes of symptoms are excluded [4, 5].

The protean and persistent neurobehavioral symptoms of PTLDS are considered to be unrelated to neuroborreliosis in which a multifocal inflammation of the peripheral nervous system (causing: cranial neuropathy, radiculopathy, or multiple mononeuropathy) or, seldomly, of the central nervous system is observed. However, this nosological entity is still under debate and is, in some ways, considered an anchoring bias [6].

Here we present the case of a patient that, following Borrelia infection, presents with progressive behavioral and cognitive symptoms, clinically resembling bvFTD and with widespread cortical hypometabolism at ¹⁸F-FDG PET. In this case, the temporal relationship between the onset of symptoms and Lyme disease may have contributed to the delayed diagnosis.

Table 1

Our patient’s neuropsychological performance (raw scores, corrected scores and cut-off values) on tests for memory, attention, language, constructional praxis, executive functions and the comprehensive neuropsychiatric profile

Cognitive Domain	Neuropsychological Assessment	Patient’s Raw Score	Patient’s Corrected Score	Cut-Off
General Cognitive Abilities	Mini-Mental State Examination [8]	19	18.49	23.8
General Cognitive Abilities	Clinical Dementia Rating [9]	2	N.A.	0.5
Memory	Digit Span [10]	4	3.75	>3.75
Memory	Visuo-Spatial Span [10]	3	3 (Z = –1,55)	–1.5 <Z+1.5
Memory	Short Story Memory Test [10]	4.3	3.3 (Z = –4,17)	–1.5 <Z+1.5
Attention	Attentive Matrices [10]	13	10.5 (Z = –4,99)	–1.5 <Z+1.5
Language	Phonemic Verbal Fluency Test [11]	19	15.3	17.35
Language	Semantic Verbal Fluency [10]	6.75	3.5	7.25
Language	Token Test [10]	18.5	16.75	26.5
Constructional Praxis	Design Copy Test [11]	6	5.6 (Z = 2,26)	–1.5 <Z+1.5
Constructional Praxis	Apraxia Test [12]	5	N.A.	6
Executive Functions	Clock Drawing Test [12]	4	N.A.	7
Executive Functions	Cognitive Estimation Test [12]	3	N.A.	4
Neuropsychiatric Profile	Neuropsychiatric Inventory (NPI) F X G [13]	42	N.A.	>29

CASE REPORT

A 61-year-old woman was admitted to our Centre for cognitive disorders in 2016. Her clinical history included: remote surgery for removal of melanoma in the right leg, hysterectomy for fibroma and chronic autoimmune thyroiditis with mild subclinical hypothyroidism. Also, no family history of cognitive impairment or neuropsychiatric disturbances was reported. At the age of 57, she received a diagnosis of Borreliosis from a high specialty center for Lyme disease in the North East of Italy, on the basis of: the typical erythema migrans; positive IgM and result confirmed on both enzyme-linked immunosorbent assay (ELISA) and western blot (in two distinct evaluations) [7]. She was then treated with doxycycline 200 mg/day for 21 days. It is important to point out that throughout the first six years of illness the patient was examined and treated by other Centers specialized in infectiology, thus they examined her not from the pure “neurodegenerative perspective” and some investigations lacked of relevant information that might have been interesting for our clinical work.

After a few weeks, she started to experience non-specific symptoms such as: depressed mood, fatigue, and apathy and, as a consequence, she was submitted to a further 14 days of treatment with doxycycline 100 mg twice a day. Following the onset of depression and apathy, the patient developed marked anxiety associated with panic attacks and behavioral disturbances, for which, she was referred to the local psychiatric service, where her depressive-anxious symptoms were treated with a benzodiazepine and an antidepressant therapy. Nevertheless, her clinical condition deteriorated overtime and her behavioral symptoms became evident, the patient developed: socially inappropriate behaviors; hyperorality with excessive food intake (with a preference for sweets); excessive smoking habits; aberrant motor activity and compulsive disinhibited behaviors (ringing others’ doorbells at night). A diagnosis of Major Depressive Disorder with psychosis was established and she was started on mood stabilizers together with antipsychotics, including lithium 300 mg twice a day and olanzapine 5 mg/day. In order to exclude a condition of neuroborreliosis, the patient was then admitted to the Neurology Department of the Local Hospital in 2014.

The diagnostic work-up also included a cytological examination of the cerebrospinal fluid (CSF) through a lumbar puncture, in order to exclude Creutzfeldt-Jakob disease and neuroborreliosis. The liquor analysis showed normal protein level of 28 mg/dL, glucose of 68 mg/dL, and 1 leucocyte per uL; immunological evaluation with ELISA was negative for IgG and IgM antibodies anti B. burgdorferi in CFS and serum; PCR for B. burgdorferi in CSF and blood was negative. Total tau was 125 pg/ml and western blot for 14-3-3 on CSF was negative. The level of amyloid-β was not assessed and our patient is not willing to receive a lumbar puncture again.

Besides, the computerized tomography performed during the hospitalization in the Neurology Department showed that a moderate degree of atrophy of the frontal lobes and the enlargement of lateral ventricles were present already at that time. For a second time, the patient received a diagnosis of Major Depressive Disorder and was again referred to the psychiatric service. Sensitivity to light, touch, and sounds was absent, as well as joint paint. Parallel to such mood and behavioral disorders, the patient started to experience memory impairment and significant attention deficits. After one year, the patient had lost her independence in performing most of activities of daily living and had to rely on her family for support. Ultimately, in 2016, the Psychiatric Service referred the patient to our Center to have her undergo neuropsychological assessment.

During the first visit, the clinical data of the infectious disease were re-evaluated together with the infection specialist that confirmed the diagnosis of Lyme disease and excluded a possible neuroborreliosis.

On the other hand, normal routine blood examinations, thyroid hormones dosage, and an endocrinology evaluation excluded the presence of hypothyroidism. The neurological examination showed that the patient was alert, partially oriented, and collaborating. She featured ideomotor slowness and ocular motility was preserved, although slightly limited in upward conjugated movements. Cranial nerves were normal and hypomimia was evident. Additionally, she had no global or segmental strength or any sensory deficits. Slight hypertonia was present, with a subtle prevalence on the left. Gait was normal but arms’ swing was absent. She had hyperreflexia with a nuanced prevalence on the left, Babinsky was negative, and primitive reflexes were present.

Her son stated that the patient featured insight on her condition at the onset of the depressive symptoms, while she had no full awareness of her condition as soon as she started experiencing cognitive impairment and behavioral disturbances.

As she featured the clinical criteria for probable bvFTD, we decided to perform a ¹⁸F-FDG PET, an amyloid-β PET, and specific genetic testing. The patient already underwent a structural MRI short before the admission to our Center.

The clinical workup included:

Neuropsychological evaluation: during the tests, the patient was vigilant and appeared motivated, yet she easily renounced and often needed reassurance. Ideomotor slowness and hypomimia were evident also during the performance of the neuropsychological battery. Mini-Mental State Examination raw score was 19, 18.5 corrected for age and education [8] and Clinical Dementia Rating was 2 [9]. Digit span was at lower reference level as well as visuo-spatial span (Z = –1.75) [10]. Memory deficits were evident in the Short Story Memory Test (Z = 4.17). The attention domain, measured with Attentive Matrices Test (Z = –4.99), was severely impaired [10], as well as the language domain, both in semantic and verbal fluencies. Also, oral comprehension resulted defective with a Token test score of 16.75, with a reference value of 26.5 [10]. Praxis functions, measured with Design Copy Test [11] (Z = –4.99) and Apraxia test (5/6) [12] were moderately impaired too. Executive functions, measured with Cognitive Estimation Test (3/5) [12] and the Clock Drawing Test (4/10) [12] were below normal ranges too. Finally, the neuropsychiatric profile resulted altered (Neuropsychiatric Inventory Frequency x Gravity = 42) [13] with an involvement of: delusions, depression, anxiety, and apathy (all of the neuropsychological data are summarized in Table 1).

Neuroimaging: Structural MRI images were visually assessed considering the main areas of atrophy in FTD: anterior cingulate, orbitofrontal cortex, anterior temporal, medial-temporal, and posterior areas [14]. Representative structural MRI T2 FLAIR in coronal slices shows frontal atrophy with moderate involvement of the anterior cingulate cortex and mild involvement of the frontal-insular and anterior temporal (Fig. 1C, D), while the orbito-frontal regions appear to be relatively spared (Fig. 1A, B), as well as the medial-temporal areas on coronal FLAIR sequences (Fig. 1D). T1 MRI sagittal slices shows mild widening of the posterior cingulate and parieto-occipital sulci. Importantly, on the same slices, a moderate-severe atrophy of the frontal motor cortices can be appreciated bilaterally (Fig. 1E, F).

¹⁸ F-FDG PET: metabolic evaluation with fluorodeoxyglucose ¹⁸F-FDG PET was also performed. PET was analyzed by visual inspection. The PET scan shows a moderate-to-marked diffuse hypometabolism in all cerebral areas with a severer involvement of the structures of the left lobe. Also, mild hypometabolism can be observed in the left striatum (Fig. 2A).

DAT scan: slight hypoactivity of the right putamen (Fig. 2B).

Amyloid-β PET: negative (Fig. 2C).

Genetic testing: Considering the clinical phenotype and age as well as the penetrance of mutations responsible for genetic FTD, we analyzed the C9ORF72 gene and evaluated progranulin (GRN) plasma levels. Genomic DNA was extracted from peripheral blood samples using standard procedures (Flexi Gene DNA Kit, Qiagen). C9ORF72 genotyping was carried out by repeat-primed polymerase chain reaction and sequencing. GRN plasma levels were determined by using commercial ELISA kit according to the procedure of the manufacturer (AdipoGen, Korea) and were found to be within normal range (132 pg/mL; NV >61 pg/mL), suggesting the absence of haploinsufficiency mutations. We carried out this analysis on the basis of previous data, showing that mutations in GRN and Chromosome 9 Open Reading Frame C9ORF72 hexanucleotide expansion are associated with psychiatric phenotypes [15, 16], however, no mutations were detected.

Fig.1

MRI T2 FLAIR coronal slices showing frontal atrophy with moderate involvement of the anterior cingulate cortex and mild involvement of the frontal-insular and anterior temporal regions (C, D), the orbito-frontal regions are relatively spared (A, B), as well as the medial-temporal areas on coronal FLAIR sequences (D). The T1 MRI sagittal slices shows mild widening of the posterior cingulate and parieto-occipital sulci and a moderate-severe atrophy of the frontal motor cortices (E, F).

Fig.2

¹⁸F-FDG PET was visually inspected and shows moderate-to-marked diffuse hypometabolism in all cerebral areas with a severer involvement of the structures of the left lobe. Higher intensities (red) indicate areas of higher metabolic activity. B) DAT scan was visually inspected and shows slight hypoactivity of the right putamen. C) Negative Amyloid-β PET.

According to current criteria [2] the patient was diagnosed with probable bvFTD.

DISCUSSION

We presented the case of a patient diagnosed with a clinically probable bvFTD with onset of symptoms progressively developing following a diagnosis of Lyme disease and with widespread cortical hypometabolism at ¹⁸F-FDG PET. On the basis of the neuropsychological evaluation, the neuropsychiatric profile and the morphostructural changes observed in MRI, the patient was diagnosed with probable bvFTD whereas in the previous six years the patient had been considered firstly as a case of PTLDS and, secondly, as a case of depression with psychotic symptoms.

Frontotemporal dementia, firstly described by Arnold Pick in 1892 [17], has been extensively studied and the relative literature is growing in content and data. Clinically, bvFTD encompasses a variety of deficits including: motivation, reward, personality, executive functions, language and attention. Pathologically, 40% of cases are associated with the accumulation of microtubule-binding protein tau, while more than half of the cases are associated with TDP-43 and FTLD-TDP [2]. More recently, researchers have tried to classify bvFTD into subtypes according to: patterns of atrophy, “functional networks” [18] and underlying pathology [19].

In our patient, the clinical profile fulfils the most recent criteria that were proven to improve diagnostic accuracy in a pathologically confirmed sample of bvFTD patients [2]. Nevertheless, given the pervasive manifestation of bvFTD, there are still many diagnostic challenges associated with it and, as a consequence, this disease tends to be underestimated. In particular, the psychiatric profile associated with bvFTD could lead to a misclassification of the underlying neurodegenerative disorder. Lanata et al. suggested that the large proportion of misdiagnosis may be caused by the lack of biomarkers for primary psychiatric disorders and the limited use of FTLD-related biomarkers by psychiatrists [20].

On the other hand, the neuropsychiatric aspect of Lyme disease has been described since the early nineties [21, 22] and the development of mood disorder has also been reported [23]. For this reason, the symptoms initially developed by our patient could have been ascribable to the infectious disease. However, the progression of the symptomatology and the absence of neuroborreliosis [24], made the diagnosis of PTLDS unlikely [25]. Very few studies suggest a possible relationship between dementia, Lyme disease, and brain changes [26 –29] and, to our knowledge, cognitive deficits as complex and profound as those we detected and ¹⁸F-FDG PET findings have never been reported in cases of Lyme disease without neuroborreliosis [30].

For what concerns the ¹⁸F-FDG PET findings, the widespread hypometabolism observed in our patient might reflect the advanced stage of the disease rather than the brain metabolic counterpart of the PTLDS [29, 31]. Although it is not a predominant “frontal” or “temporo-limbic” metabolic pattern, it is important to point out that a high case-to-case variability has been previously found [32]. Furthermore, it is worth considering that misdiagnoses of bvFTD and low accuracy of ¹⁸F-FDG PET have been also reported in patients subsequently receiving a psychiatric diagnosis [33].

Regarding the DAT scan findings, the reduction of uptake in the putamen is not unusual in FTLD and it may embody the expression of the mild extrapyramidal sign of bradykinesia observed in the present case [34].

With respect to the genetic and GRN serum level dosage, no mutations in GRN were found, and also C9ORF72 HREs expansion analysis was negative.

Overall, with the presented case we are not implying any causative relationship between Lyme disease and the subsequent development of the neurological condition of the patient. Indeed, our patient’s CSF was negative for neuroborreliosis, thus excluding an involvement of the infection through the central nervous system. Ultimately, we believe that such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing a contributory role. This case suggests the opportunity to delineate more clear-cut neuropsychological and neuroradiological criteria to be associated to the laboratory testing. Standardized work-up is hoped to help the clinician to distinguish the neuropsychiatric sequelae of a Lyme disease from those of a primarily neurodegenerative disease, likely avoiding anchoring biases.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-0524r1).

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