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The European Journal of Psychiatry

versión impresa ISSN 0213-6163

Eur. J. Psychiat. vol.25 no.1 Zaragoza ene./mar. 2011




Clinical and functional outcome in a subject with bipolar disorder and severe white matter hyperintensities



Gianluca Serafini*; Maurizio Pompili*,**; Massimiliano Angelone*; David Lester***; Paolo Girardi*; Roberto Tatarelli*

* Department of Psychiatry - Sant´Andrea Hospital, "Sapienza" University of Rome. Italy
** McLean Hospital - Harvard Medical School, Boston. USA
*** The Richard Stockton College of New Jersey. USA





Background and Objectives: Neuroimaging studies have found higher rates of white matter hyperintensities (WMHs) in patients with bipolar disorder (BD) of all ages, although whether BD is associated with increased rates of WMHs independently from age and cerebrovascular risk factors is still matter of debate. The outcome of BD associated with severe WMHs is generally poor, but several authors have suggested that some factors could have a protective role in BD. The aim of the present study was to report the two-year follow-up of a woman with BD type I and severe WMH/PWMH lesions who was taking high concentrations of vitamin-D in her nutrition, as well as taking lithium and haloperidol as treatment.
Case presentation: A 76-year-old woman was hospitalized for a mixed state BD. She had severe WMHs. She took lithium and haloperidol during the hospitalization and was euthymic at discharge as well as after two-years of follow-up. Her nutrition had a high concentration of Vitamin-D. Unfortunately, it was not possible to give her a second MRI.
Conclusions: Although there was probable persistence of WMHs, the patient improved in both mood and quality of life. The possible protective effect of lithium and Vitamin-D is discussed.

Key words: White matter hyperintensities; Bipolar disorder; Lithium; Vitamin-D; Outcome.


Background and objectives

Neuroimaging studies have found higher rates of WMHs in patients of all ages with bipolar disorder (BD), most frequently localized in the frontal lobes and the frontal/parietal junction1. WMHs may indicate astrogliosis, demyelination and loss of axons and may be relatively more common in older patients with BD, reflecting an interaction of the disease with processes of normal aging. However, WMHs are also associated with several pathological conditions among older individuals2. As a result of this, the meaning of these lesions in BD is still unclear.

Although there have been inconsistent results in the research on this issue, WMHs are considered to be negative prognostic factors, associated with treatment resistance, increased hospitalization rates, cognitive impairment and increased suicide risk in individuals with BD3,4.

However, several other factors may play a protective role in BD. Tsai et al.5 reported that psychiatric treatment, including medication with antipsychotics or lithium, could be a protective factor against early natural death. Here, we present the case of a 76-year-old woman who had had a BD for twenty-one years and had, in addition, severe WMH/PWMH lesions, who was admitted to our psychiatric hospital for a mixed state. The patient gave written consent before being included in the study.


Case presentation

A 76-year-old woman was admitted to our psychiatric hospital in a mixed state. She had elevated mood, social withdrawal, weight loss and inner tension, and she was agitated and dysphoric. She also presented with delusional persecutory ideas and auditory hallucinations.

She had been diagnosed as having BD type I at the age of 55, but she had never been hospitalized. She had ten previous mood episodes (5 depressive, 3 manic and 2 mixed episodes), but she had no actual comorbid psychiatric condition.

She had no brain injuries at birth, data confirmed by her sister during the psychiatric interview. She had no history of hypertension, diabetes, or heart failure. Her cholesterol level was 150 mg/dl. She had normal blood pressure values during the hospitalization (as confirmed by the Holter electrocardiogram). She took lithium at 150 mg/die from the illness onset, but recently this had been stopped without any specific reason given. A brain magnetic resonance imaging scan revealed severe confluent periventricular WMHs (see Fig. 1). The presence of WMHs was assessed by a neuroradiologist blind to all clinical information, using the modified Fazekas rating scale6.


While hospitalized, she was treated with haloperidol 2 mg and lithium carbonate 300 mg daily. She improved rapidly and was discharged after two week of hospitalization. At discharge, her Young mania rating scale score (YMRS)7 had decreased from 30 to 12 and the Hamilton depression rating scale score (HDRS)8 from 26 to 16. The physical component (PC) score of the Short Form Health Survey (SF-36)9 had increased from 10 to 22 and mental component (MC) score from 10 to 18. She was euthymic for the following two-years of follow-up. Psychometric measures were repeated every year and remained stable.

She was a vegetarian and frequently ate fat fish, cod-liver oil, eggs and milk which have high concentrations of vitamin-D. Serum lithium levels were within the range (0.6-1.2 meq/L) and were monitored every month. Her Mini Mental State Examination score (MMS)10 increased from 22 to 26 and remained stable during the follow-up period. Unfortunately, it was not possible to administer a second MRI because she was surgically implanted with a left hip prosthesis for coxarthritis.



The most relevant finding of this case report is that, despite the presence of severe WMHs, our patient was euthymic during the two-years of follow-up and had good psychosocial functioning.

In most patients with BD, there is a gap between clinical remission and functional outcome11,12 and, after a relapse, only 40%, although euthymic, achieve their premorbid functional status13. Therefore, it is important to identify which factors may contribute to this disability. Recently, Rosa et al.14 suggested that the poor functional outcome in patients with BD was predicted by the previous number of mixed episodes, current subdepressive symptoms, the previous number of hospitalizations and an older age. Our patient had no previous mixed episodes, no current subdepressive symptoms, no previous hospitalizations and a later age of onset of bipolar illness, but, interestingly, she also had a nutrition rich in vitamin-D which is a multipurpose steroid hormone vital to health and increasingly implicated in the pathology of cognition and mental illness. The vitamin-D receptors and the vitamin-D activating enzyme 1-alpha-hydroxylase are widely distributed in the human brain15. Hypovitaminosis D may be common among older adults, and it is associated with poor executive performance in patients with mood disorders16. Vitamin-D receptors activate neurons implicated in the regulation of behaviour, stimulate neurotrophin release and protect the brain, presumably by buffering antioxidant and anti-inflammatory defenses against vascular injury17. Langub et al.18 reported that vitamin-D plays a neuroprotective role (e.g., an anti-oxidative effect) for hippocampal cell survival, presumably mitigating cellular homeostasis. Although poorly understood, the eventual neuroprotective effect of vitamin-D in subjects with mood disorders may be mediated by their antioxidative and/or anti-inflammatory action.

Our patient took lithium which may promote neurogenesis both in short and long term treatment19. Lithium treatment has demonstrated a robust neuroprotective role in preventing apoptosis of neurons, and this has relevant clinical implications20,21. Although no direct evidence of lithium's ability to improve cognitive performance has been found, lithium-induced increases in gray matter volume may be associated with a positive clinical response, particularly during weeks 10-12 and maintained through 16 weeks of treatment22.



Although limited to the present case report, our findings suggest that lithium therapy could play a protective role for patients with BD. The additional therapeutic role of vitamin-D in a subgroup of patients with BD could provide a safe, low cost treatment, as well as providing additional advantages for general bone health. However, prospective longitudinal studies are required to understand the pathophysiological processes involved in these processes in BD.



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Gianluca Serafini, MD
Department of Neuroscience
Mental Health and Sensory Functions, "Sapienza"
University of Rome, Sant' Andrea Hospital
Via Grottarossa 1035-1039, 00189, Rome, Italy
Tel. +39-0680345280
Fax +39-0680345342

Received: 12 January 2010
Revised: 5 August 2010
Accepted: 14 September 2010

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