Case report: a giant arachnoid cyst masking Alzheimer’s disease

Intracranial arachnoid cysts are usually benign congenital lesions, filled with cerebrospinal fluid and covered by arachnoidal cells and collagen. They typically develop between the surface of the brain and the cranial base or on the arachnoid membrane. Widespread usage of non-invasive neuroimaging modalities have made the diagnosis of arachnoid cysts one of the most common incidental findings: While in a healthy population slightly less than 3% of subjects were found to have intracranial abnormalities [1], the prevalence of arachnoid cysts has been estimated to be between 0.3 and 1.7% of the general population and highest in the pediatric subpopulation [2‐5]. Most intracranial arachnoid cysts remain clinically silent so that patients may live their entire life without symptoms, even if cysts are large. For symptomatic cysts, when patients present with signs of normal pressure hydrocephalus (gait disturbance, incontinence and dementia) and speech impairment, surgical cyst decompression may lead to an improvement [6, 7].

We here present the case of a 66-year-old man with a large left-hemispheric cyst and mild cognitive impairment. Although at first glance a cognitive decline seemed to be related to the anatomic anomaly, further extensive evaluation using different imaging modalities and biomarkers was required to reveal Alzheimer’s disease rather than the arachnoid cyst as underlying cause for the cognitive deterioration. With this case report we not only aim at presenting the coincidental finding of a large cyst and a neurodegenerative disease where the neurodegenerative component might have been overlooked without adequate diagnostic tools. We also discuss that arachnoid cysts mask and may further augment neurodegenerative processes. We thus suggest a modus operandi for the diagnosis and treatment of patients with arachnoid cysts and suspected cognitive impairment.

The patient presented at the memory clinic for the assessment of slowly progressive short-term memory deficits over the course of the past 3 years. He reported troubles in finding words, forgetting names of friends and items he intended to buy in the supermarket. He described a normal developmental history with no developmental delay or psychosocial abnormalities. He remembered that he was teased by other children because of his large head and that even as a small child he would have required headgears in adult size. He denied any history of head trauma, toxic exposure, chronic headaches or another neurological or psychiatric illness. The patient had never used any psychiatric drug before. There was no history of learning disorders, hyperactivity or significant academic difficulties as well as no form of substance abuse. He completed high school and professional training as a bank accountant, where he continued to work for 27 years followed by several years of work in a communication company. The patient has stable and good social relationships. He is retired but still assisting in a pharmacy by delivering medicine to clients.

At the time of examination, his spouse confirmed cognitive decline over several years, and reported a tendency of participating less in conversations, while otherwise his psychosocial functioning was normal. She also had noticed an impaired orientation in new surroundings and episodes of confusion in group discussions or family meetings.

Three years ago he had consulted a neurologist for his memory impairment, who initiated a structural cranial MRI. This revealed a large left frontotemporal cerebrospinal fluid-filled cyst with a cross-sectional area of 6 × 14 cm compatible with a Type III arachnoid cyst according to Galassi classification [14] of middle cranial fossa arachnoid cysts (Fig. 1). Two subsequent MRIs within the following 3 years did not show any size progression. On repeated neurosurgical evaluation it was decided for watchful waiting and against surgical intervention because of the absence of focal neurological signs and cyst size progression.

Our patient revealed two potential etiological factors for the development of cognitive decline: The giant arachnoid cyst reducing his neuronal plasticity and Alzheimer’s disease [30]. As shown in our case report an extensive work-up was required to dissect the contribution of each disease entity although their interaction remains a matter of debate. Our case particularly illustrates that a giant arachnoid cyst may leave the brain tissue intact but might mask an underlying neurodegenerative disorder such as Alzheimer’s dementia. It also illustrates the diagnostic value of biomarkers, e.g. medio-temporal lobe atrophy (Scheltens Score 2) and increased Amyloid-PET imaging. Thus, the diagnosis of prodromal Alzheimer dementia (AD) / mild cognitive impairment due to AD was established in this patient [31].

Although elevated tracer binding can also be found in normal older volunteers without cognitive deficits, with the proportion of “positive cases” ranging from 10 to 30% depending on the age of the cohort and the threshold for defining the pathological tracer enhancement [32‐35], the preponderance of current literature proposes that enhanced amyloid-beta signal in non-demented subjects is associated with decreased episodic memory performance and structural/functional brain changes suggestive of incipient Alzheimer’s disease [36]: In a retrospective study [37], amyloid-beta positive PET scans were more common in subjects with declining cognitive test scores (70%) than in those with stable scores (17%).

Our findings in the cognitive assessment are in line with previous studies showing a rather heterogeneous picture of cognitive deficits across different domains, lacking clear specificity of cognitive and neuropsychological changes following prodromal AD/MCI due to AD. The often expansive lesions due to arachnoid cysts may cause a reorganization of cortical functions. This reorganization can vary to a large extent between patients, which is reflected in changes in a variety of cognitive functions. According to a review article [38], these functions encompass verbal perception and memory, complex verbal tasks, visuospatial functions and visual attention and dichotic perception and memory [7] of which not all have to be impaired in every patient. The interpretation of cognitive impairments thus provide some evidence on the specificity of the reorganization and compensation, yet, this needs to be treated with caution as various factors co-determine such effects.

Furthermore, the application of different imaging modalities and biomarkers helped the neurosurgeons to triage our patient: the patient was followed-up by the neurosurgeons several times for a surgical intervention as clinically a mild cognitive impairment became apparent. However, when Alzheimer’s disease was revealed as the leading underlying cause of cognitive decline rather than tissue damage from the arachnoid cyst, the neurosurgeons decided against a cystectomy. As there was no cyst size progression and no further neurological symptoms a benefit from the surgery was highly questionable for the patient.

Moreover, this case study is also an impressive demonstration of neuronal plasticity fully compensating for even large intracranial pathologies. Most intracranial arachnoid cysts remain clinically silent [1], reflecting the tremendous plastic capacity of the central nervous system to compensate for even large structural abnormalities. As arachnoid cysts are usually congenital, the brain fully adapts to the special circumstances during development, a condition which could be also found in our patient: The 66-year old lived his life rather unaffected by the giant arachnoid cyst, he would not be aware of until the age of 63. The patient remembers of wearing headdresses of adults at a very young age and being teased because of his head size as a child suggesting the congenital nature of the arachnoid cyst. Similar phenomena have been described in children with intractable seizures who underwent surgery with resections of entire brain regions or callosotomy [39, 40].

The application of different neuroimaging modalities revealed structural and functional perseveration of the left hemisphere despite being displaced and squeezed by the giant cyst: Representation of finger movements was sustained at a rather similar position in the left hemisphere compared to the right sensorimotor cortex. Interestingly, bilateral representation in particular of the left hand was revealed and even pronounced in the right hemisphere, which might be explained by the ambidexterity of the patient, being originally left-handed but trained right-handed. We chose a sensorimotor task for the fMRI experiment to map in particular the left hemisphere, as the giant arachnoid cyst had a strong mass effect on this brain region. The goal of the fMRI was to detect any functional map shift and loss of functional integrity (together with structural alterations found in the DTI (Fig. 2)), which could also impact cognitive functions. Since we did not aim at detecting the neuronal correlate of the cognitive decline but at understanding the structural and functional integrity despite the giant cyst, a cognitive task with fMRI would have been less helpful. Although we cannot rule out that memory function is still impaired despite of the intact motor function, normal sensorimotor integration may be also correlative for cognitive performance as discussed by others [16, 18] and vice versa: Abnormal sensorimotor integration correlates with the cognitive profile in neurological diseases [41].

However, it remains a matter of debate, if the plastic compensational mechanisms of the brain decline over time, and thus expose patients with even clinically silent brain pathologies to cognitive impairment. Although a connection between arachnoid cysts and cognitive sequelae has been proposed for over 20 years [42], the impact of clinically silent cysts on cognitive decline remains largely unknown due to the subtlety of dysfunction. Rabiei et al. [43] found that subjects with and without cysts had the same frequency of headache, dizziness, previous head trauma, cognitive impairment and depressive symptoms without an increased prevalence of dementia, depression, epilepsy or previous hip fracture. Nonetheless a relationship between the onset of Alzheimer’s pathology and the arachnoid cyst might be plausible: As previously postulated by Silverberg et al., 2003 [44] we speculate that the existence of the arachnoid cyst may modify intracranial pressure ratios, leading to reduced perfusion and metabolism in the surrounding cortical regions. Furthermore, the cyst might perturb CSF circulatory pathology which might result – along with genetic factors such as apolipoprotein E4 Aβ -in the accumulation of amyloid-β peptide, microtubular associated protein τ (MAP τ) and other toxins. An increase in the steady state concentration of Aβ influences Aβ aggregation which is causally und pathognomonic in Alzheimer’s disease [45, 46]. In particular soluble Aβ is potentially neurotoxic affecting normal neuronal function and even causing cell death [47, 48]. Since our patient presented with apolipoprotein E ε3/3 wildtype allele, this genotype will not have contributed to the early manifestation of Alzheimer dementia. Thus it may be speculated that the impaired CSF flow dynamics due to the giant cyst might have caused reduced amyloid clearance inducing Alzheimer pathology. Longitudinal studies in patients with huge arachnoid cysts might become important to detect symptoms of cognitive decline early and thereby open a window of opportunity for early therapeutic intervention to prevent or slow down further cognitive deterioration [49].

One major lesson to be learned from the case illustrated here is, that patients presenting with large intracranial brain cysts and cognitive decline require a closer look and pure clinical examination and structural MRI might be insufficient to triage patients either to neurosurgery or watchful waiting. The review and study presented here may thus initiate further discussion for a modus operandi for patients with large intracranial cysts: We suggest [1] a detailed neurological and neuropsychological examination as well as MRI of the brain [2]. The repetition of all procedures is crucial to detect the development of cognitive decline and neurological symptoms over time. The cyst may also become symptomatic due to growth progression and may thus require surgical intervention [3]. An additional neurodegenerative component should be evaluated either by biomarkers in the cerebrospinal fluid or amyloid-PET imaging [4]. Additional fMRI may become a useful assessment to study functional integrity and for risk analysis of cognitive deterioration: Patients with less prominent functional map changes and no neurodegenerative comorbidity may be at lower risk for a cognitive decline. In contrast, large functional map shifts may be associated with cognitive impairment due to a decline of plastic compensation in aging.

The case presented here illustrates that in patients with large intracranial brain cysts and cognitive impairment pure clinical examination and structural MRI might be insufficient to triage patients. Our case report suggests the diagnostic value of rigorous neuroimaging modalities including DTI, fMRI and amyloid-PET imaging as well as biomarkers in the cerebrospinal fluid to distinguish tissue damage induced by large cysts versus a neurodegenerative pathology as underlying cause of cognitive decline.