Agenesis of Corpus Callosum and Frontotemporal Dementia

Abstract

Agenesis of corpus callosum (AgCC) is a congenital malformation characterized by total or partial absence of corpus callosum with a good neuropsychological profile. Frontotemporal dementia (FTD) is the third most common cause of cortical dementia, and it is characterized by alterations in personality and social relationship, often associated with deficits in attention, abstraction, planning, and problem solving. Herein, we report a case of a 73-year-old woman presenting with FTD associated with primary AgCC. The possible “causal or casual” relationship between these 2 different conditions should be investigated in large prospective studies.

Introduction

Corpus callosum (CC) is the largest connective structure in the central nervous system (CNS) with 190 million axons engaged in interhemispheric connection for sensory, motor, and visuomotor integration, transferring information between the left and the right hemispheres. Agenesis of corpus callosum (AgCC) is a congenital malformation characterized by total or partial absence of CC. Agenesis of corpus callosum occurs at least in 1:4000 live births and in 3% to 5% of individual assessed with neuroimaging for neurodevelopmental disorder. ¹ Moreover, the combined prevalence of AgCC and CC hypoplasia was estimated to be 1.8 per 10 000 live births. ² Agenesis of corpus callosum is a fetal neurodevelopmental disorder with a complex pathogenesis, having genetic, infectious, vascular, or toxic causes. ^1,3 The congenital abnormality is frequently associated with other pathological conditions, including brain structural anomalies (ie, hydrocephalus, cists, etc), neurological dysfunctions (ie, epilepsy), extracerebral malformations, chromosome abnormalities, viral infections, toxic syndromes, and metabolic diseases. ^1,4

Primary AgCC refers to a specific condition characterized by isolated AgCC, observed on magnetic resonance imaging (MRI), with a good intellectual profile.

However, deficit in problem solving, pragmatic language and communication, and in emotion processing with a limited impact on general cognitive abilities are considered to be the main neuropsychological findings in primary AgCC. ^1,5 Herein, we report a 73-year-old woman presenting with frontotemporal dementia (FTD) associated with primary AgCC.

Case Description

A 73-year-old woman came to our observation for short-term memory impairment associated with anxiety and depressive mood. Her family history was negative for neurodegenerative and psychiatric disorders, and her psychomotor development was normal since she reported graduating from high school. She was affected by diabetes mellitus, treated with metformin (500 mg three times daily), and by arterial hypertension, treated with β-blockers with good pharmacological blood pressure control. In the past 3 years, the patient had fear, unfocused worries, restlessness, and muscular tension. This symptomatology worsened in the last period, being associated with emotional indifference for her family members, and diminished social interest.

Moreover, her relatives have also noted episodes of socially inappropriate behavior with impulsive actions and, sometimes, disinhibition and increased consumption of chocolate and other sweets. Standard blood tests, as well as folate, vitamin B12, homocysteine, and thyroid hormone levels, were within the normal range. General and neurological examinations were also normal. At neuropsychological assessment, she presented mild memory impairment, partial disorientation in time and space, constructive apraxia, and a dysexecutive syndrome with a 22/30 Mini-Mental State Examination (MMSE) score. The patient was able to perform daily living activities, although she didn’t want to go out by herself. Episodes of urinary incontinence were also reported by the patient and the caregiver. A brain MRI demonstrated a total absence of CC (Figure 1), besides a mild to moderate bilateral frontotemporal atrophy (Figure 2). A brain single-photon emission computed tomography (SPECT) was also performed, showing a more posterior than anterior hypoperfusion pattern (Figure 3).

Figure 1.

A and B, Inverted T2 and T2-weighted sagittal images demonstrate the absence of corpus callosum and radial orientation of gyri. C, T2-weighted axial shows parallel nonconverging ventricles, communication between third ventricle and interhemispheric fissure, and colpocephalic aspects of occipital horns. D, The absence of CC determines alterations in the white matter tracts, which indeed course longitudinally instead of transversely, Probst bundles well-delineated in coronal FLAIR image. CC indicates corpus callosum; FLAIR, fluid attenuation inversion recovery.

Figure 2.

Moderate bilateral frontotemporal atrophy with enlarged sulci.

Figure 3.

Perfusion SPECT shows a global cortical hypoperfusion, mainly involving the posterior lobes. SPECT indicates single-photon emission computed tomography.

As diagnosis of unspecified cognitive impairment associated with anxious–depressive syndrome was posed, the patient was prescribed choline per os and sertraline 50 mg/d. Nevertheless, despite medical treatment, at 1 year follow-up, the patient started presenting with behavioral abnormalities, including anhedonia, apathy, sleep disorders, and restlessness, with a moderate improvement concerning anxiety. Moreover, she had some compulsive and repetitive behavior, including hand washing and checking locks.

Cognitive impairment, with regard to the dysexecutive syndrome, becomes moderate, and she had to be helped in the performance of many of the activities of daily living. Indeed, the MMSE score was 15/30, Attentive Matrix score was 12, Trail Making Test part A score was 287 whereas the part B was not administrable, and Constructive Apraxia Test score was 9. Interestingly, episodic memory and visuospatial functions were relatively spared, suggesting FTD diagnosis.

Sertraline was thus titrated up to 150 mg/d and mirtazapine (30 mg/d) prescribed with a moderate improvement in depressive symptoms and sleep alteration.

Discussion

To the best of our knowledge, this is the first reported case of asymptomatic primary AgCC associated with FTD. Indeed, the onset of neuropsychiatric symptoms together with the gradual progression of neuropsychological ones and neuroimaging findings—but SPECT—supported the FTD diagnosis.

Frontotemporal dementia is the third most common cause of cortical dementia, following Alzheimer dementia (AD) and Lewy body disease. The most common manifestations of behavioral FTD are the alterations in personality and social relationship, including inertia and loss of volition or social disinhibition and distractibility, deficits in attention, abstraction, planning, and problem solving, as in a “dysexecutive” syndrome. Moreover, the cognitive decline and neuropsychiatric deficit have a gradual progression and are then related to disabilities in everyday life. ⁶

According to the revised criteria for FTD, “possible” behavioral variant of FTD (bvFTD) requires 3 of 6 clinically discriminating features, that is, disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile, whereas “probable” bvFTD adds functional disability and characteristic neuroimaging.

Although SPECT was not so typical from FTD (ie, a more posterior than anterior hypoperfusion pattern), we may affirm that our patient was possibly affected by the bvFTD, since she accomplished the new clinical diagnostic criteria ⁷ and MRI showed a moderate frontotemporal atrophy. Although AgCC has been associated with numerous neuropsychiatric disorders, including schizophrenia ⁸ and autism, ⁹ the link between psychiatric symptoms and AgCC is still unclear.

A recent systematic review by Siffredi et al ⁴ concerning the neuropsychological profile in individuals with AgCC has highlighted that the variability in neuropsychological outcome in individuals with AgCC was deeply linked to the cerebral plasticity in fetal evolution, the compensatory mechanisms in CNS, and the clinical comorbidities.

In their work, by using the British Neurological Surveillance Unit, Taylor and David described 37 individuals affected by AgCC associated with different diseases, that is, epilepsy in nearly two-thirds, intellectual impairment in half of the sample, and psychiatric disorders in around one-third. ¹⁰ Interestingly, the authors also reported on a case of early-onset dementia that has been considered as a casual finding. ¹⁰

To this end, Rasgon et al ³ described for the first ever time a case of a 57-year-old man with clinical and neuroradiological characteristics of early-onset AD, presenting a gradual onset of psychiatric symptoms at the age of 54, before the occurrence of neuropsychological deficit after about 3 years. As recently demonstrated, ¹¹ callosal atrophy is present even in early AD and subsequently accelerates; thus, the rate of CC atrophy is associated with cognitive decline in patients with AD.

However, although different cognitive patterns, ranging from severe neuropsychological deficit to mild deficiencies in social cognition, occasionally manifested in AgCC, most often the presence of AgCC is associated with subtle deficits in cognitive and intelligence only in test performance.

Indeed, Brescian et al ¹² have recently described an 88-year-old man with AgCC and minimal associated neuropsychological impairment concerning, in particular, the coordinated use of both hands in tactile and proprioceptive tasks. Interestingly, the authors illustrated the strong influence of cerebral plasticity in the variability of clinical outcomes in the context of congenital malformation.

We are unable to know whether the absence of the CC has played a role in the development of patient’s neuropsychological symptomatology, since our findings are based on a snapshot at one point in time and not on a long-term follow-up. According to the other few reported cases, ^3,4 in our patient (with a normal psychological and neuromotor development and life-long functional independence) neuropsychiatric abnormalities represented the initial clinical sign, since she had been presenting an invaliding anxiety disorder with interpersonal distance, followed by moderate dysexecutive syndrome only in the late adulthood. Therefore, we agree with Brescian et al in that congenital-based interhemispheric disconnectivity does not preclude the development of efficient cognitive functions, and its presence in patients affected by dementia may only be a casual finding.

Conclusion

Although the link between AD and callosal degeneration is well documented, the possible relationship between dementia, including FTD, and AgCC is still unclear. Thus, further prospective studies should be fostered to investigate this intriguing “causal or causal” link.