Atypical presentation of progressive young onset dementia

Abstract

We present the case of a 34-year-old Jordanian woman who was referred to mainstream mental health services because of irritability, agitation, loss of appetite, withdrawal from family activities and sleeping difficulties. She was initially diagnosed with major depressive disorder but subsequently showed very poor response to antidepressant therapy. Her presentation gradually and dramatically progressed into full blown dementia within couple of years. Brain MRI showed atrophic cortical changes and subcortical white matter alterations consistent with Alzheimer’s dementia. Brain PET scan revealed reduction in cerebral glucose metabolism in temporoparietal areas bilaterally most consistent with Alzheimer’s dementia. There was a strong family history of early-onset dementia. A final diagnosis of young onset dementia was made, and unfortunately, she passed away at the age of 44 years.

Background

Young onset dementia (YOD) can have a devastating effect on patients and their families. Initial clinical presentations of such cases can be misleading with some non-specific symptoms present at the onset. This paper reports a case of YOD in a female patient with initial presentation in her mid-30s. And despite a strong family history of dementia, this case was initially misdiagnosed as major depressive disorder. However, with progression of her cognitive decline and findings from neuroimaging scans, she was subsequently diagnosed with YOD.

Case presentation

A 34-year-old Jordanian woman, who worked as a secretary and was living with her husband and children in Qatar, presented to the psychiatric outpatient clinic in Doha for the first time with irritability, agitation, loss of interest, social withdrawal, loss of appetite complicated by loss of weight and insomnia. Initial diagnosis of major depressive disorder was made, and she was subsequently commenced on escitalopram 20 mg daily.

Few months later, it became clear that her response to antidepressants was poor. She gradually became forgetful and was using reminders to help her carry out household activities. Within 2 years of her initial presentation, she began to lose some of her work skills such as typing which has culminated in losing her job. At the same time, her husband noticed that she was becoming very slow in performing home activities and was eventually unable to take care of herself and her children. She once forgot to turn off the stove, which caused a fire in the house. She was then commenced on memantine 20 mg daily but with no clear benefit observed. Three years after initial presentation, she had difficulties in recognising family members and significant loss of language with word-finding difficulties. It was reported that she was urinating on herself without being distressed by it, and 6 months later she completely lost urine control.

She also had an episode of generalised tonic–clonic convulsions with loss of consciousness for which she was admitted to the medical ward and was commenced on lamotrigine 50 mg twice daily.

On admission, mental state examination revealed a middle-aged woman with poor grooming and hygiene, poor eye-to-eye contact, easily irritable, not responding to questions with evident psychomotor agitation present. Her affect was irritable and speech was incoherent and irrelevant. She showed hallucinatory behaviour as she was clearly mumbling to herself.

Cognitive assessment using Mini Mental State Examination revealed that she was not oriented to time, place or person. She was able to register three items correctly but recalled none. She was unable to do the serial 7s, serial 3s or days of the week backward. She was able to name two items correctly; however, she could not read, repeat or write a sentence. She was not able to carry out the three-stage command or copy the intersecting pentagons. She scored 6 out of 30. Moreover, she could not carry out the clock-drawing test as she only drew a circle but nothing else.

Medical and surgical history was unremarkable. No history of hypertension, diabetes mellitus, dyslipidaemia, stroke or other chronic illness was found. No history of head injury was reported.

She was a heavy smoker between 18 and 40 years of age, but with no history of alcohol consumption or substance misuse.

Physical examination was unremarkable.

Family history revealed that her mother, aunt from mother’s side and her elder brother had similar problem, and were diagnosed with dementia in their mid-30s.

Early development and childhood was uneventful. She had a degree in English literature and worked as a secretary for 15 years. She was married and had four children.

Investigations

Complete blood count (CBC), urea and electrolytes, lumber puncture including cerebrospinal fluid (CSF) analysis and liver function test were all within normal limits.

HIV and Venereal Disease Research Laboratory test (VDRL) were negative, and inflammatory markers were within normal limits. Standard EEG was done twice during her inpatient stay at the advanced stage of the illness. In the first one, patient was not cooperative. The second one showed a dominant background rhythm that consists of irregular, moderate amplitude (20–30 mkv) and slow activity in theta range (4–6 Hz). Posterior dominant frequency was about 7 Hz and not attenuating to eye opening.

Over the frontal leads, beta activity was still preserved. Irregular polymorphic delta intermixed with theta waves were seen bilaterally in central-parietal-temporal derivations without asymmetry. Photic stimulation was performed at varying frequencies with no significant changes. Hyperventilation was not performed. There was no هepileptiform activity noted.

Neuroimaging

Brain CT showed cortical atrophy and ventricular enlargement.

Brain MRI (figure 1) showed cortical and subcortical brain atrophic changes which were more evident in the temporal and occipital areas. A focus of bright T2 and fluid-attenuated inversion recovery signal intensity was noted in the posterior temporal region in the subcortical white matter.

Figure 1.

Brain MRI showed cortical and subcortical brain atrophic changes in the temporal and occipital regions.

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain (figure 2) showed markedly reduced cerebral glucose metabolism involving both temporal and parietal lobes bilaterally. It also showed decreased cortical uptake in the temporal and parietal regions with relative sparing of the sensorimotor cortex, occipital region and basal ganglia, which is consistent with Alzheimer’s dementia (AD).¹

Figure 2.

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed markedly reduced FDG metabolism involving both the temporal and parietal lobes bilaterally, in addition to moderately diminished FDG uptake in lateral frontal areas bilaterally.

Genetic testing

This was offered but family declined.

Differential diagnosis

There is a wide range of differential diagnoses including AD, vascular dementia, Lewy body dementia, Parkinson’s disease dementia, multiple sclerosis, Huntington’s disease and normal pressure hydrocephalus.

Treatment

Following initial presentation, the case was treated as major depressive disorder and was commenced on escitalopram 20 mg daily but with very poor response. Follow-up assessments showed marked cognitive decline with signs of dementia. She was subsequently diagnosed as young onset dementia, moderate to severe type, and was commenced on memantine 20 mg daily. She developed tonic–clonic convulsions and lamotrigine 50 mg twice daily was added. Both escitalopram and lamotrigine were discontinued at a later stage as she had no further convulsions, and she continued on memantine 20 mg once daily.

Outcome and follow-up

After a short hospitalisation in the psychiatric ward, her family requested transfer back to her home country; Jordan. She was completely dependent on others with evident progressive deterioration. Sadly, she passed away in her home country.

Discussion

We presented a case of progressive YOD in a Jordanian female patient who initially presented with depressive symptoms. Diagnosing such a case as well as the required work-up is challenging.^2–4 Most cases of progressive cognitive dysfunction in young adults are caused by metabolic disturbances, substance misuse and alcohol.² Apparently, this case appears to be familial. Her mother, aunt and elder brother had similar condition in their mid-30s, and they passed away in their late-40s. Hence, a genetic cause is the most likely aetiological factor. The most common cause of familial early-onset dementia is AD, caused by a genetic mutation of dominant inheritance. Mutations in Presenilin 1 are the most common genetic cause of early-onset familial AD. These mutations are fully penetrant with a median age of 43 years.⁵ Unfortunately, the family of this patient declined genetic testing.

Initial presentation with depressive symptoms in this case is of a particular interest in view of the frequently reported comorbidity of depression in AD.^{6 7} In this patient, both structural and functional brain imaging did report significant temporal lobe changes bilaterally, and this is significant in view of the postmortem studies which had reported greater pathological changes in the hippocampus (temporal lobe structure) in AD patients with a history of depression compared with those without such history.^{8 9} Moreover, there is evidence to suggest that loss of 5-HT_1A receptors is correlated with early depressive symptoms in patients with AD.¹⁰ These 5-HT_1A receptors exist in high density in the cerebral cortex, raphe nucleus and some temporal lobe structures such as hippocampus and amygdala.^{11 12} One can postulate in this case, from the above findings, the initial depression was a manifestation of an early loss of 5-HT_1A receptors in the hippocampus and amygdala in the temporal lobes. This neuropathological change gradually progressed to other brain areas leading to a dementing illness.

Brain imaging plays an important role in making the diagnosis in such cases.¹³ Along with our clinical evaluation, findings from brain MRI (figure 1) and FDG-PET (figure 2) provided support in making the diagnosis of AD.

Management of cases with YOD should include pharmacological and non-pharmacological approaches.¹⁴ Pharmacological interventions such as cholinesterase inhibitors and N-methyl-D-aspartate antagonists can help reduce the progression and improve the quality of life.¹⁵ In addition, pharmacological interventions can help in managing symptoms associated with YOD such as hallucinations and delusions. Non-pharmacological interventions such as respite care, support to families and day care programmes are of great help in the management of cases of YOD.^14–16 Some of the potential modifiable risk factors are traumatic brain injury, heavy alcohol consumption, psychiatric illness and cardiovascular disease.¹⁷ Presence of any of these factors could make the case for primary prevention for YOD.¹⁸

Cases with YOD represent a major burden on families and on the society at large.^{19 20} Not like late-onset dementia, YOD affects patients during their productive years, and this can have a devastating effect on their work, family and social life.²¹

Patient’s perspective.

Husband’s perspective: It was a very frustrating experience as I have to change my life priorities to accommodate taking care of my wife, kids and be able to support them financially.

Learning points.

• Differential diagnosis of progressive cognitive decline in young age is wide and requires clinical, imaging and other diagnostic tests.

• In early-onset dementia, particularly younger than the age of 40, atypical presentations should be kept in mind.

• Early-onset dementia remains a rare condition, and when it happens, it represents a major burden on the patient, his/her family and the society.