Secondary Logo

Journal Logo

Some neuropsychiatric and MRI manifestations in patients with multiple sclerosis

Allam, Mahmoud M.; EL-Hamady, Mohamed M.; Morad, A.A.; Faheem, M.K.; Morsi, Badr A.E.

Middle East Current Psychiatry: January 2015 - Volume 22 - Issue 1 - p 44–56
doi: 10.1097/01.XME.0000458885.02819.92
Original articles
Free

Background Neuropsychiatric abnormalities are common in multiple sclerosis (MS) patients. Cognitive dysfunction affects ∼40% of MS patients. Advances in neuroimaging are increasing our understanding of the pathogenesis of these disorders.

Aim This study aimed to assess the possible neurological and psychiatric complications and cognitive impairment in MS patients and to correlate the psychiatric symptoms with clinical types, severity, and MRI findings in MS patients.

Participants and methods This is a cross-sectional descriptive study that was carried out on 25 patients diagnosed with definite MS according to McDonald’s criteria. All patients were subjected to a semi-structured interview that included demographic data and full neurological and psychiatric examination, Expanded Disability Status Scale (EDSS) evaluation, Mini-Mental State Examination (MMSE), and MRI brain with assessment of the lesions number, site, and brain atrophy.

Results This study included 25 adults, 19 women and six men. They ranged in age from 22 to 55 years, mean age 33±9 years. The mean disease duration was 6.4±3 years. Sixty-four percent of the patients were married. Sixty-four percent of the patients had the relapsing remitting type of MS. Fatigue was the most prevalent symptom (96%), followed by sphincter troubles, (80%) visual symptoms (76%), dizziness (64%), sexual dysfunction (60%), and pain (56%). EDSS showed that 44% of the patients had moderate disability, 32% of the patients needed intermittent or constant unilateral assistance, and 24% of the patients needed constant bilateral support. On applying the Structural Clinical Interview for DSM-IV Axis I (SCID-I), it was found that depression (60%), dysthymia (60%), and generalized anxiety disorder (68%) were the most prevalent psychiatric presentations. For the MMSE, 24% of the patients showed an MMSE score between 17 and 25 and 4% the patients showed scores less than 17. Assessment of MRI brain showed that atrophic brain changes were present in 72% of the patients. All the patients studied had supratentorial plaques and 44% had frontal plaques. Infratentorial lesions were present in 72% of MS patients.

Conclusion and recommendations Attention should be focused on the other important presentations of the disease such as psychiatric disorders and cognitive impairments, and a comprehensive biopsychosocial neuropsychiatric approach should be adopted, which is essential for optimal care of patients with MS.

aDepartment of Neurology, Faculty of Medicine, Cairo University, Cairo

bDepartment of Neurology and Psychiatry, Benha University, Benha, Egypt

Correspondence to Mohamed M. El-Hamady, MD, Department of Psychiatry, Benha University Hospital, Benha, Egypt Tel: +20 100 660 5602; fax: +20 226 00541; e-mail: mohelhamady@yahoo.com

Received February 10, 2014

Accepted October 27, 2015

Back to Top | Article Outline

Introduction

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system (CNS), destroying the myelin and the axon to variable degrees and producing significant physical disability within 20–25 years in more than 30% of patients. The hallmark of MS is symptomatic episodes that occur months or years apart and affect different anatomic locations 1.

It is more common in higher latitudes of north Europe and Australia, but less prevalent in the tropics and the Arabian Peninsula 2.

Historically, the Kurtzke classification has designated many Middle Eastern countries as being low-risk zones for MS, but recent studies have shown that the crude incidence of MS in this region ranges from 31 to 85/100 000 individuals, and that the annual incidence is increasing 3–6.

The etiology of MS is believed to involve an interplay between genetic and environmental factors resulting in immunological-mediated inflammatory responses within the CNS. The process is targeted either at one or more structural components of the white matter (WM) or against extrinsic antigens integrated with the host nervous system 7.

The disease is characterized clinically by episodes of focal disorders of the optic nerve, spinal cord, and brain, which remit to a varying extent and recur over a period of many years 8.

Almost 42% of MS patients had clinically significant depression (as defined by the epidemiological studies depression scale) and it was noted that depressive symptoms are more likely to occur as the disease worsened and there is an additional period of depression shortly after diagnosis. Other factors consistent with more severe depressive symptoms include young age, less education, and lack of social support 9.

For a number of reasons, cognitive impairment may be considered the most severe effect of MS. It is cognition that makes us human and allows for maximal human function 10.

Ongoing disease progression leads to cerebral atrophy and impaired cognitive function. Unlike physical function, cognitive impairment does not remit. The most common deficits in MS patients are in memory, learning, attention, and information processing 11.

Unfortunately, however, cognitive impairment may be among the least recognized of the symptoms as it is a ‘hidden’ disability. In a population of MS patients, up to two-thirds are reported to have cognitive impairment 12.

In many cases, the clinical evidence is sufficient to establish the diagnosis of the disease, but investigations are used to document the anatomical dissemination of the lesion, to confirm the presence of intrathecal inflammation, and to exclude conditions that may mimic demyelinating diseases.

Computerized topography and double-dose delayed contrast enhancement yield higher number of MS cerebral lesions, but these are insensitive compared with MRI, which is an important diagnostic tool, and can also be used to assess disease load, activity, and progression, and distinguish between acute and chronic lesions. Also, it plays a role in assessment of the outcome of therapy 13.

Cerebrospinal fluid analysis provides different but complementary information in patients suspected of having MS. Increased cerebrospinal fluid gamma globulins occur in most MS patients 14.

Intrathecally synthesized oligoclonal IgG levels in cerebrospinal fluid and serum are both specific and sensitive for the diagnosis of MS. Electrophysiological studies using visual, auditory, somatosensory evoked potentials, and central motor conduction using the techniques of magnetic brain stimulation are used clinically to identify the presence of sub clinical lesions 15.

Back to Top | Article Outline

Aim of the work

This study aimed to assess the possible neurological and psychiatric complications and cognitive impairment in MS patients and to correlate the psychiatric symptoms with clinical types, severity, and MRI findings in MS patients.

Back to Top | Article Outline

Participants and methods

This is a cross-sectional descriptive study that was carried out on 25 patients diagnosed with definite MS according to McDonald’s criteria and its revision 16.

The research sample included 25 patients who were selected randomly from the Maadi MS clinic in the Armed Forces Military Hospital in Maadi, Egypt, during the period from 2008 to 2010.

Sixteen patients had relapsing remitting multiple sclerosis (RRMS), six had secondary progressive MS, and four had primary progressive MS.

Back to Top | Article Outline

Inclusion criteria

We selected a study group that included patients between 15 and 55 years of age as this is the usual age distribution for MS.

During the assessment and protocol administration, all patients were fully conscious according to the Galasco Coma Scale.

All patients were fully diagnosed to have definite MS.

All the patients were subjected to the following: a semi-structured interview that included demographic data, and a full neurological and psychiatric examination.

Expanded Disability Status Scale (EDSS) evaluation 17.

Mini-Mental State Examination (MMSE) 18.

Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I) 19.

MRI brain with assessment of the lesions number, site, and brain atrophy.

The assessment period started with an informal discussion about the individual’s experience with MS; this was to build up a rapport, ensure confidentiality, and explain the purpose of the study. We obtained an informed consent from each participant before proceeding with the assessment protocol.

Participation in this study was completely free and voluntary and would not have any impact on the drug regimen. Anonymity of the patients in the study was maintained and they were ensured that the results of the study would not be shared with a third party and would only be used for scientific purposes. Any participantcould exit from the study at any time without giving justification.

Back to Top | Article Outline

Exclusion criteria

We excluded MS patients younger than 15 years of age or those older than 55 years of age as both age groups are beyond the usual age of distribution of MS, patients with suspected MS, with a previous history of psychiatric disorders, with other comorbid medical or neurological disorders such as diabetes mellitus, renal diseases, hepatic diseases, epilepsy, others demyelinating disorders, or autoimmune diseases, among others.

Back to Top | Article Outline

Statistical analysis

Statistical presentation and analysis of the present study were carried out using the mean, SD, SE, the Mann–Whitney U-test, and the χ2-test using V17 statistical package for scientific studies for Windows (IBM Corporation., Endicott, New York, USA).

Back to Top | Article Outline

Results

The demographic criteria of the studied group were as follows:

  • The study included 25 adults, 19 women and six men.
  • The age range of the participants was between 22 and 55 years, mean age 33±9 years; 44% of the patients ranged in age from 15 to 30 years, 28% ranged in age from 30 to 40 years, and 28% ranged in age from 40 to 52 years.
  • The mean disease duration was 6.4±3 years and 56% of the patients had duration between 5 and 10 years.
  • Eighty-eight percent of the patients were highly educated and 22% had an intermediate level education.
  • Sixty-four percent of the patients were married and 36% were single.
  • Sixty-four percent of the patients had the RRMS, 20% had the secondary progressive type of MS, and 16% had the primary progressive type of MS.

EDSS was in the range of 0.5–8. EDSS was less than 3 in 44% of the patients, which indicates moderate disability in one functional system. EDSS grade 3–6 was found in 32% of the patients, which indicates a range from moderate disability to intermittent or constant unilateral assistance (cane, crutch, or brace). An EDSS grade of more than 6 was found in 24% of the patients, which indicates constant bilateral support up to essentially restricted to bed.

There was no statistical significance in the degree of physical disability according to the EDSS score among the MS patients studied.

On applying the SCID-I (Table 1), it was found that depression (60%), dysthymia (60%), and GAD (68%) were the most prevalent. However, compulsion (32%), panic disorder (16%), and hallucinations (20%) were the least prevalent.

Table 1

Table 1

There was a very high statistical significance in the presence of SCID-I symptoms in the MS patients studied.

For the MMSE score (Table 2), it was found that:

Table 2

Table 2

  • The MMSE score ranged from 16 to 30, mean 26±4.
  • Most patients (72%) had an MMSE score above 25.
  • Twenty-four percent of the patients showed an MMSE score between 17 and 25.
  • Four percent of the patients showed scores less than 17.

There was no statistical significance in the score of MMSE among the MS patients studied.

In terms of the medications received by the MS patients studied, 96% of the patients received corticosteroids, either intravenous or oral, but most of them were no longer on continuous treatment.

Immunomodulation (Interferon) was received by 68% of the patients, and 64% received an immunosuppressant either without or before and after Interferon.

Assessment of MRI brain of MS patients showed that atrophic brain changes were statistically significant, found in 72% of the patients (with χ2=4.00 and P=0.0455).

MRI brain of MS patients showed that all the patients studied had supratentorial plaques and 44% had frontal plaques. Infratentorial lesions were present in 72% of MS patients.

The presence versus absence of MS plaques in various sites of the brain showed a high statistical significance (with χ2=19.000 and P=0.001).

In this section of the results, we will show the relationship between the SCID-I and the different neurological and psychiatric variables.

When assessing the relationship between marital status and the SCID-I disorders, it was found that there was a significant statistical relationship between being married (48%) and depression in comparison with being single (12%) (with χ2=4.167 and P=0.041) in MS patients. There was also a relationship between being married, dysthymia (44%), and GAD (52%), although this was statistically insignificant.

On assessing the relationship between age and the SCID-I disorders, it was found that there was a statistically significant relationship between increasing age, depression, and hypomania among MS patients. There was a relationship between increasing age, dysthymia, and panic disorder, although this was statistically insignificant.

On examining the relationship between the different types of MS and the SCID-I disorders, it was found that there was a statistically significant relationship between the RRMS (32%) and mania in comparison with the secondary progressive and primary progressive types of MS, where both showed no cases (0%) (with χ2=6.618 and P=0.037). There was also a relationship between the RRMS and depression (36%), dysthymia (40%), and GAD (40%), although this was statistically insignificant.

On using the Mann–Whitney U-test, there was also a statistically significant relationship between increasing disease duration and SCID-I mania (with mean±SD=4.500±1.195 and Z=2.206, P=0.027), panic (mean±SD=10.250±3.862 and Z=2.245, P=0.025), and hypochondriasis (with mean±SD=11.000±1.414 and Z=2.023, P=0.040).

The Mann–Whitney U-test also showed a statistically significant relationship between increased number of MS attacks and SCID-I somatization (with mean±SD=8.286±3.450 and Z=2.136, P=0.034).

Results showed a relationship between the EDSS score and the SCID-I disorders among the MS patients studied. When the data were analyzed using the Mann–Whitney U-test, a relationship was found between high EDSS and depression (P=0.285) and mania (P=0.914), although this was statistically insignificant (Table 3).

Table 3

Table 3

Table 4 also shows the relationship between the MMSE and the SCID-I disorders among the MS patients studied; the results were statistically insignificant for all the SCID-I disorders.

Table 4

Table 4

On assessing the relationship between the different neurological symptoms at the time of examination and the SCID-I disorders, it was found that there was a statistically significant relationship between the absence of pain and mania (with χ2=4.588 and P=0.032) as shown in Table 2).

There was also a statistically significant relationship between the presence of fatigue and hallucinations (with χ2=4.167 and P=0.041) as shown in Table 5.

Table 5

Table 5

However, on examining the data of the other neurological symptoms, namely, visual symptoms, sexual dysfunction, dizziness, and sphincter troubles, in relation to the SCID-I disorders, the results were statistically insignificant.

The results also showed a statistically significant relation between MRI brain frontal lesions and SCID-I hallucinations (with χ2=7.955 and P=0.005) (Table 6). It was also found that there was a statistically insignificant relationship between MRI brain atrophic changes, the number of plaques, and the SCID-I disorders.

Table 6

Table 6

Back to Top | Article Outline

Discussion

Demographic data

In this study, 25 patients from Maadi Military Armed Forces Hospital in Cairo were examined. This number is considered relatively small, but this is because it was difficult to obtain a large number as the prevalence of the disease is not high in Egypt. It has been reported that the prevalence of MS increases as geographical distance from the equator increases 20. Additional factors are the difficulty in early diagnosis, and the expensive investigations and work-up required to diagnose this disease in Egypt.

In this study, there were 19 women (76%) and six men (24%) diagnosed with definite MS. It has also been reported that MS affects twice as many women as men 20. A female-specific increase in the incidence of MS has also been documented 21–23.

The patients in this study ranged in age between 22 and 55 years. The mean age was (33±9) and this is in agreement with the usual age distribution of MS 24. The results showed that 44% of the patients were between 15 and 30 years of age, 28% were between 30 and 40 years of age, and 28% were between 40 and 52 years of age.

On assessing the relationship between age and the SCID-I disorders, it was found that there was a statistically significant relationship between increasing age, depression, and hypomania among MS patients. There was a relationship between increasing age, dysthymia, and panic disorder, although this was statistically insignificant.

This was in accordance with other studies that found an age-related increase in the prevalence of depression that persisted after control of multiple variables 25.

It can also be surmised that with age, patients seem to lose hope of recovery and believe that they are handicapped by their illness, and thus become more depressed and anxious.

When assessing the relationship between marital status and the SCID-I disorders, it was found that there was a statistically significant relationship between being married (48%) and depression in comparison with being single (12%) among MS patients. There was also a relationship between being married, dysthymia (44%), and GAD (52%), although this was statistically insignificant.

We found that the rate of depression was significantly high among married patients; this might be because of the lack of social support and the fact that most of them were women that are anxious about their fertility and decrease in their chances to lead normal secure marital lives. In our study, 60% of patients had sexual dysfunction, which may be an additional contributing factor.

On examining the relationship between the different types of MS and the SCID-I disorders, it was found that there was a statistically significant relationship between the RRMS (32%) and mania 26 in comparison with the secondary progressive and primary progressive types of MS, where both showed no cases (0%). There was also a relationship between the RRMS and depression (36%), dysthymia (40%), and GAD (40%), although this was statistically insignificant.

In MS patients, the lifetime prevalence of bipolar affective disorder is twice the prevalence in the general population. This increase cannot be attributed to the effects of steroids treatment alone. Unlike major depression, there may be a genetic predisposition to bipolar affective disorder in some female MS patients 27.

Currently, the four major types of MS include RRMS, primary progressive, secondary progressive, and progressive relapsing. RRMS accounts for ∼80–85% of all MS cases, with a clear sex difference, with more females being affected than males (female : male ratio 1.6 : 1). Clinically, RRMS is characterized by clinical relapses (or exacerbations) with full or partial recovery, followed by interval periods of clinical stability and absence of disease progression. A relapse is defined as an episode of neurological disturbance for which causative lesions are likely to be inflammatory and demyelinating in nature. There should be a subjective report (supported by objective findings) or objective observation that the event lasts for at least 24 h 13,16,28. Each relapse of MS should be separated from the last relapse by at least 1 month of clinical stability 13. Clinical relapses in RRMS are associated with surges in peripheral immune system activity and up to one-third of cases are triggered by an underlying infection, such as urinary or upper respiratory tract infection.

There was also a statistically significant relationship between increasing disease duration and SCID-Ι mania, panic, and hypochondriasis.

The increasing disease duration may lead to longer periods of treatment, making the patients vulnerable to drug-induced mania. The increased disease duration may also lead to panic in patients that they may not recover, and may thus in turn lead to hypochondriasis.

The burden of accepting a lifelong, progressive, and incurable illness likely also plays a role in the development of depression. Shorter duration of illness (<1 year) has been associated with depression, perhaps reflecting the difficulty of adjusting to a new diagnosis of this chronic, unpredictable illness; this finding highlights the need for frequent screening for depression in newly diagnosed MS patients 29,30.

However, it was found that shorter duration of MS was also associated with a greater likelihood of significant depressive symptoms, but the pattern of illness progression was not 9.

Results also showed a statistically significant relationship between increased number of MS attacks and SCID-I somatization. This result was in agreement with that of Sarisoy et al. 31. This may be interpreted by the fact that patients are usually in a state of anticipation of their next attack, which makes themsusceptible to somatization.

Back to Top | Article Outline

Neurological symptoms

In terms of the distribution of the neurological symptoms among the group of MS patients studied, Table 7 shows that fatigue was the most prevalent symptom (96%), followed by sphincter troubles, (80%), visual symptoms (76%), dizziness (64%), sexual dysfunction (60%), and pain (56%). Neurological symptoms were present to a highly statistically significant degree in the study group of MS patients.

Table 7

Table 7

Owing to the progressive nature and widespread distribution of lesions in the gray and WM of human CNS, the clinical manifestations of MS are quite variable. MS symptoms consist of motor, sensory, brainstem, visual, cerebellar, and neuropsychiatric symptoms. Motor symptoms in MS mainly originate from corticospinal tract involvement and patients complain of weakness, heaviness, stiffness, or even pain in the affected limbs. Development of demyelinating lesions in the corticospinal tract may occur at the medullary pyramids, basis pontis, cerebral peduncles, deep hemispheric WM, or, most commonly, within the spinal cord. Patients may develop hemiparesis/hemiplegia or quadriparesis/quadriplegia. The lower extremities are usually more affected than the upper extremities. Upon neurologic examination, the corticospinal involvement manifests as weakness along with spasticity and hyperactive reflexes, with clonus and the presence of a bilateral Babinski reflex. Motor deficits and cerebellar involvement can particularly lead to the risk of falls.

Cerebellar manifestations in MS result from vermian and hemispheric cerebellar (a favorite location for MS) demyelinating lesions, and clinically present with gait ataxia, dysmetria, intention tremor on the finger-to-nose test, dysdiadochokinesia, difficulty with the heel-to-shin test, rubral tremor, and failure to perform on tandem gait examination 32.

In terms of the distribution of the neurological symptoms among the group of MS patients studied, fatigue was the most prevalent symptom (96%). This result was in agreement with that of Caceres et al.33.

We found that there was a statistically significant relationship between fatigue and hallucinations (Table 5). The presence of hallucinations may be interpreted by the high use of immune-suppressing drugs, non steroidal anti-inflammatory, and drug–drug interactions. In addition to the other physical symptoms of MS, fatigue also has detrimental effects on patients with MS. Fatigue places extra strain on the individual and makes any activity much more difficult, requiring increased effort to accomplish simple tasks; such stress may be of a psychotic level.

A high incidence of sphincter troubles was also found among the group of MS patients studied (80%). The high incidence of bladder dysfunction in MS was first identified by Oppenheim 34. Several series have since reported an incidence of urinary symptoms in ∼75% of all patients with MS 35. The most common symptom is urgency of micturition, which occurs in 24–86% of all patients with bladder dysfunction 36. Urinary frequency has been reported in slightly fewer patients, the incidence varying between 17 and 65%, with the incidence of urge incontinence varying between 34 and 72% in patients with bladder dysfunction 37. This may be attributed to the autonomic manifestations associated with spinal cord lesions.

The visual symptoms were also highly prevalent (76%). Neuromyelitis optica (Devic’s disease) is an MS-like inflammatory demyelinating disease characterized by longitudinally extensive lesions of the spinal cord expanding over several cord segments and optic neuritis (involvement of the optic nerves and chiasm) 38,39.

Certain clinical manifestations in MS indicate brainstem involvement in MS. Patients with MS may develop impairments in ocular motility, such as horizontal as well as rotatory, upbeating, and downbeating nystagmus, and may complain of images jumping in front of their eyes (oscillopsia). Unilateral or bilateral internuclear ophthalmoplegia (INO), a disorder of conjugate lateral gaze, is frequently encountered in MS patients. INO results from lesion(s) of the medial longitudinal fasciculus, which is a heavily myelinated tract within the brainstem that connects the paramedian pontine reticular formation–abducens nucleus complex on one side to the oculomotor nucleus of the opposite side. An INO is characterized by failure of the adduction of the eye ipsilateral to the lesion while the contralateral eye fully abducts and develops a horizontal dissociated nystagmus. Other abnormalities of ocular motility, which may be observed as part of MS, consist of one-and-a-half syndrome, skew deviation, paresis of single cranial nerves innervating extraocular muscles (III, IX, and IX), horizontal or vertical gaze paresis, and impairment of smooth visual pursuit. Involvement of the lower parts of the brainstem is associated with unilateral or bilateral facial paresis, dysarthria, nasal speech, pseudobulbar palsy, vertigo, tinnitus, dysphagia, blepharospasm, and rarely hearing loss, although the latter is rare 32.

A large number of MS patients initially present with optic neuritis, which clinically manifests as dimming of the vision unilaterally or bilaterally, photophobia, and pain worsened by ocular movement. Upon neuro-ophthalmologic examination, varying degrees of visual acuity loss, central scotoma, papillitis (swollen optic nerve head with hemorrhages or exudates), or normal optic disk (in cases of retrobulbar optic neuritis) are detected. In addition, these patients have impairment of color vision, prolonged visual-evoked potentials, and a positive ‘swinging flash-light test’, which points toward an afferent pupillary defect (also known as Marcus Gunn pupil), as well as various forms of visual field defects 32.

Dizziness was prevalent in 64% of the MS patients in our study. This was in agreement with other studies reporting that dizziness is one of the common presenting symptoms of MS, and is usually because of loss of balance 40.

In our study, we found that 60% of the patients had sexual dysfunction. There were significant correlations between the presence of sexual dysfunction and depression, dysthymia, panic disorder, GAD, somatization, hypochondriais, and delusions, but these were not statistically significant.

Sexual dysfunction is prevalent in MS, perhaps one of the most common problems associated with the disease, and was found in 60% of the patients in the study. Sexual dysfunction impacts quality of life significantly. It may be attributed to the autonomic manifestations associated with the spinal cord lesions. The Massachusetts Male Aging Study found that 52% of men experience occasional sexual dysfunction 41. Another large US study found that 43% of women and 31% of men in the general population experience occasional sexual dysfunction 42. In these studies, a number of factors were found to increase the risk of sexual dysfunction: age older than 40 years, chronic physical illness, and the use of a number of different medications. An Australian study found that only 20% of MS patients were completely free from problems with intimacy and/or sexuality 43.

Pain was also highly prevalent among the group of MS patients studied (56%).This result was in agreement with that of Harrison et al. 44, who reported that pain affects around 63% of patients with MS. Sensory symptoms in MS may represent demyelinating lesions of the myelinayed axons of the posterior columns (fasciculi gracilis and cuneatus) or spinothalamic tracts. Patients commonly report tingling, numbness, tightness (band-line tightness around the trunk when there is myelitis) or a feeling of an electric shock traveling down the spine upon flexion of the neck (Lhermitte’s sign). In addition, MS is a potentially painful disease and several painful syndromes, such as trigeminal neuralgia glossopharyngeal neuralgia 45, radicular pain, and ‘central pain’, may occur during the course of the disease. Central pain is observed in 15–85% of MS patients 32.

On assessing the relationship between the different neurological symptoms at the time of examination and the SCID-I disorders, it was found that there was a statistically significant relationship between the absence of pain and mania as shown in Table 2.

The presence of mania may be attributed to the high use of immune-suppressing drugs and non steroidal anti-inflammatory drugs to counteract the associated pain.

Back to Top | Article Outline

EDSS

The EDSS grade was in the range of 0.5–8. EDSS grade was less than 3 in 44% of patients, which indicates moderate disability in one functional system. EDSS grade 3–6 was found in 32% of patients, which indicates moderate disability to intermittent disability, or requirement of constant unilateral assistance (cane, crutch, or brace). EDSS grade higher than 6 was found in 24% of patients, which indicates requirement of constant bilateral support up to essentially restricted to bed.

There was no statistical significance in the degree of physical disability according to the score of EDSS among the MS patients studied.

Results also showed the relationship between the EDSS score and the SCID-I disorders among the MS patients studied. There was a relationship between high EDSS, depression, and mania, although this was statistically insignificant.

Some studies have shown that physical disability is independent of depression in patients with MS 46. It was also found that depression was correlated with the degree of neurological impairment, but not with the degree of functional disability 47. However, some studies reported a correlation between depressive symptoms in individuals with MS and degree of disability 31,48.

Data on the relationship between physical disability and depression are mixed 9,29,30, although depressed patients with MS may experience the impact of their disability greater than nondepressed patients 29,30. Furthermore, physical disability in MS often leads to social isolation, loss of independence, and loss of recreational activities, factors that may contribute toward the development of depression 49. Other psychological characteristics predictive of depression in patients with MS include feelings of uncertainty about the future, hopelessness, and emotion-centered coping (as opposed to active, problem-centered coping strategies) 9.

Back to Top | Article Outline

Psychiatric symptoms

On applying the SCID-I (Table 1), it was found that depression (60%), dysthymia (60%), and GAD (68%) were the most prevalent. However, compulsion (32%), panic disorder (16%), and hallucinations (20%) were the least prevalent.

There was a very high statistical significance in the presence of SCID-I symptoms in the MS patients studied.

Psychiatric symptoms in MS are highly prevalent and are frequently overlooked in clinical settings 30,50,51. In one study of relapsing-remitting patients with MS in remission, 95% reported significant psychiatric symptoms, most frequently dysphoria (79%), agitation (40%), anxiety (40%), and irritability (35%) 52.

Major depressive disorder (MDD) is particularly common 31,53, with a lifetime prevalence rate of ∼50% 9,30,50,51 compared with a rate of 10% to 15% in the general population. Rates of suicide are also significantly higher in those with MS, and in one study, depression superseded physical disability and cognitive function as a significant determinant of quality of life 50. Several factors related to MS symptomatology, disease course, and treatment may contribute toward the very high rates of depression and its complications in patients with MS. For example, MS and depression share several neurovegetative symptoms (including fatigue, poor concentration, and disturbances of sleep and appetite), which can complicate the diagnosis of depression in this population 50. However, studies generally support the strikingly high prevalence of depression in MS patients, finding high rates of MS-associated depressive disorders even when somatic complaints are not included in the diagnostic criteria 54.

Finally, the effects of treatment for MS, particularly interferon, may occasionally cause or exacerbate depressive symptoms. Although studies have not reported a well-defined relationship between treatment with interferon and depression, they are plagued by methodological flaws, and the results are conflicting 16,55.

In terms of the medications received by the MS patients in our study, 96% of the patients received corticosteroids, either intravenous or oral. Immunomodulation (Interferon) was received by 68% of patients and 64% received immunosuppressants either without or before and after Interferon.

The aforementioned characteristics of illness (neurovegetative symptoms, physical disability, and progressive course) are not unique to MS, and yet for unclear reasons, MDD remains more common in MS than other chronic neurologic conditions that affect the CNS 30,54. MDD in MS patients has been associated with characteristic CNS changes, including cortical atrophy and lesions in specific regions of the frontal lobes, which may account for some of the differences observed 49. MDD in patients with MS, therefore, is unlikely to represent a simple reaction to the physical disability, uncertainty, and decreased independence that the illness entails, but given its prevalence, may be considered a symptom of the illness itself and reflective of CNS cortical damage 56.

Back to Top | Article Outline

MMSE

For the MMSE score, it was found that:

  • MMSE score ranged from 16 to 30, mean 26±4.
  • Most patients (72%) had an MMSE score above 25.
  • Twenty-four percent of patients had an MMSE score between 17 and 25.
  • Four percent of the patients had scores less than 17.

Any score greater than or equal to 25 points (out of 30) indicates normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10–17 points), or mild (18–24 points) cognitive impairment.

There was no statistical significance in the score of MMSE among the MS patients studied.

Table 4 also shows the relationship between the MMSE and the SCID-I disorders among the MS patients studied; the results were statistically insignificant for all the SCID-I disorders.

Cognitive deficits are common in patients with MS, with 40–65% showing some degree of cognitive dysfunction on neuropsychological testing 1,50. Cognition is often affected early during the course of illness, occasionally before the onset of physical disability 57. However, functional MRI studies indicate that the brain may adapt to compensate for these deficits, reflected by altered connectivity between different brain regions to limit the expression of pathology, a concept known as functional reorganization 58. Functional reorganization, specifically bihemispheric recruitment, in response to cognitive tasks mirrors findings from studies of motor deficits in MS patients. This effect may in part explain why observed lesions in MS do not necessarily correlate with observed deficits and why patients can recover function despite accumulating lesions 58,59. Previous studies suggest that long-term treatment with IFNβ may protect against cognitive impairment in patients with MS 60,61. Interferon was received by 68% of the patients.

The most commonly affected cognitive domains include speed of information processing, memory (particularly working memory), and attention 62–64. Depression can also lead to impairments in attention, concentration, and memory, potentially compounding deficits in cognition 56.

Back to Top | Article Outline

MRI

Assessment of MRI brain of MS patients shows that atrophic brain changes were statistically significant.

MRI brain of MS patients showed that all the patients studied had supratentorial plaques, and 44% of them had frontal plaques. Infratentorial lesions were present in 72% of MS patients.

The presence versus absence of MS plaques in various sites of the brain showed high statistical significance.

The results also showed a statistically significant relation between MRI brain frontal lesions and SCID-I hallucinations (Table 6). A statistically insignificant relationship was also found between MRI brain atrophic changes, the number of plaques, and the SCID-I disorders.

It is believed that MS patients show psychiatric disorders secondary to demyelinating lesions at the temporal lobe, the physiopathology of which is not fully known. The temporal lobe functions are language, memory, and emotion. Lesions at this brain location may cause hallucinations, mood and thought disorders, euphoria, irritability, and cognitive deficit. This brainlocation is especially associated with psychiatric alteration. In the cases reported, lesions were present on several brain locations, mainly periventricular and corpus callosum 30.

Neuroimaging studies indicate that cognitive dysfunction is associated more strongly with the degree of gray and WM atrophy rather than with MS lesion loads 59,65.

In particular, WM volume loss is related to impairment in information processing speed and working memory, likely reflecting the fact that temporarily holding and manipulating information (as in working memory) requires rapid neural communication between different brain regions through WM tracts. Gray matter (GM) volume matter loss, in contrast, is predictive of deficits in verbal memory 65.

There is also increasing evidence that GM pathology, as reflected by atrophy, is implicated in cognitive dysfunction as MS progresses 66.

Although MS is classically considered a WM disease, the involvement of GM in the pathogenic process has been confirmed by pathology studies and MRI studies. Impairment in cognitive domains such as memory, mental processing speed, attention, and executive function can occur from the early stage of the disease and tends to worsen over time, despite stable physical symptoms. WM demyelination is correlated moderately with cognitive impairment, suggesting that WM abnormalities alone probably cannot fully explain the extent of clinical symptoms in MS, including cognitive impairment. Several MRI techniques have shown the involvement of GM in MS and the association between GM damage, physical disability, and cognitive impairment 67.

It is important to keep in mind that cognitive changes may be prominent even in the absence of active or visible MS lesions and these impairments can lead to occupational difficulties and to problems in everyday function. Patients may benefit from environmental modifications (such as schedules and reminder systems) to reduce the impact of cognitive deficits 56.

MRI lesions are often clinically silent and MRI changes do not necessarily correlate well with the extent of clinical disability 68. Chronic black holes and brain atrophy are associated with greater tissue destruction and show higher correlation with disability compared with T2 burden of disease 69. MRI brain measures are used rarely for the prediction of prognosis and clinical outcome in MS.

Some studies have reported a significant correlation between the frontal lesion area on T2-weighted scans and performance on neuropsychological tests selectively exploring the frontal lobe functions 70. Other studies have found a significant correlation between frontal lobe impairment and frontal lesion volumes on T2-weighted MRI scans 71,72.

In our study, we found that there were statistically nonsignificant correlations between increasing MRI plaque number and mania, hypomania, panic, hypochondriasis, and hallucinations, but there was a slightly statistically significant correlation between decreased number of MS plaques and depression and dysthymia.

A study evaluated the frequency and location of lesions in the U-fibers and correlated these findings with neuropsychological impairment. Forty-two such lesions were detected in 28 of the 53 patients studied (53%). The majority of them were in the frontal lobe (about 65%). Scores of neuropsychological tests reflecting performance in executive control and memory were significantly different between the patients with multiple U-fiber lesions and those without any or with only a single U-fiber lesion 73.

We found that about 72% of the patients had various degrees of brain atrophy ranging from mild, moderate, to severe, and there were insignificant correlations between the MRI brain atrophic changes and SCID-I parameters, especially depression, dysthymia, hypochondriasis, obsessions, GAD, and somatizations.

No clear association between brain abnormalities was identified by MRI and depression. There is a suggestion that immune abnormalities, in association with dysfunction of the hypothalamic–pituitary–adrenal axis, may be the mechanism underlying the high lifetime risk for depression 74.

A higher lesion load in the anterior temporal lobe and the inferior medial prefrontal cortex of the dominant hemisphere as well as dominant anterior temporal lobe atrophy are associated with depression 75.

Feinstein 76 noted that there was a positive association between depression and brain lesion load and the incidence of depression seemed to increase with the deterioration of these lesion loads. In contrast to these findings, it was found that measurements of lesion load showed no significant difference between depressed and nondepressed MS patients 77.

Also, there was a statistically significant correlation between hallucinations and frontal MRI lesions. A study reported that the lesion is almost always located in the brain pathway of the sensory modality of the hallucination. They also found that the temporal lobe was the most common lesion site, followed by the frontal lobe and tissue around the third ventricle 78.

Back to Top | Article Outline

Conclusion and recommendations

Attention should be focused on the other important presentations of the disease such as the psychiatric disorders and cognitive impairments, and a comprehensive biopsychosocial neuropsychiatric approach should be adopted, which is essential for the optimal care of patients with MS.

Advances in neuroimaging are increasing our understanding of the pathogenesis of these disorders. Translating these findings into improved methods of management for patients is essential.

Professionals in the medical field such as neurologists, primary care physicians, nurses, and psychologists should be made aware of the multiproblematic aspects of MS so that a comprehensive biopsychosocial neuropsychiatric approach may be adopted, which is essential for the optimal care of patients with MS.

It is necessary to establish a MS association in Egypt with provision of every kind of support to enable management and care of Egyptian MS patients at every stage of the disease.

Table

Table

Back to Top | Article Outline

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Luzzio C, Keegan BM, Dangond F, Childers MK, Hooke EA, Huff JS, et al.. Multiple sclerosis. 2014; Available at: http://emedicine.medscape.com/article/1146199-overview#aw2aab6b2b3aa.
2. Mahad DJ, Trebst C, Kivisäkk P, Staugaitis SM, Tucky B, Wei T, et al.. Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions. J Neuropathol Exp Neurol 2004; 63:262–273.
3. Bohlega S, Inshasi J, Al Tahan AR, Madani AB, Qahtani H, Rieckmann P. Multiple sclerosis in the Arabian Gulf countries: a consensus statement. J Neurol 2013; 260:2959–2963.
4. Alroughani R, Ahmed SF, Behbahani R, Khan R, Thussu A, Alexander KJ, et al.. Increasing prevalence and incidence rates of multiple sclerosis in Kuwait. Mult Scler 2014; 20:543–547.
5. Deleu D, Mir D, Al Tabouki A, Mesraoua R, Mesraoua B, Akhtar N, et al.. Prevalence, demographics and clinical characteristics of multiple sclerosis in Qatar. Mult Scler 2013; 19:816–819.
6. Inshasi J, Thakre M. Prevalence of multiple sclerosis in Dubai, United Arab Emirates. Int J Neurosci 2011; 121:393–398.
7. Miterski B, Epplen JT, Gencik M. On the genetic contribution to selected multifactorial diseases with autoimmune characteristics. Cell Mol Biol (Noisy-le-grand) 2002; 48:331–341.
8. Minagar A, Ostanin D, Long AC, Jennings M, Kelley RE, Sasaki M, Alexander JS. Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells. Mult Scler 2003; 9:235–238.
9. Chwastiak L, Ehde DM, Gibbons LE, Sullivan M, Bowen JD, Kraft GH. Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. Am J Psychiatry 2002; 159:1862–1868.
10. Schwartz L, Kraft GH. The role of spouse responses to disability and family environment in multiple sclerosis. Am J Phys Med Rehabil 1999; 78:525–532.
11. Bagert B, Camplair P, Bourdette D. Cognitive dysfunction in multiple sclerosis: natural history, pathophysiology and management. CNS Drugs 2002; 16:445–455.
12. Greene YM, Tariot PN, Wishart H, Cox C, Holt CJ, Schwid S, Noviasky J. A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. J Clin Psychopharmacol 2000; 20:350–356.
13. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al.. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227–231.
14. Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, et al.. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 2005; 62:865–870.
15. Fuhr P, Kappos L. Evoked potentials for evaluation of multiple sclerosis. Clin Neurophysiol 2001; 112:2185–2189.
16. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al.. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121–127.
17. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444–1452.
18. Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 1992; 40:922–935.
19. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Clinician Version (Administration Booklet) 1997.Washington, DC: American Psychiatric Association.
20. Rovaris M, Comi G, Filippi M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J Neurol Sci 2006; 245:111–116.
21. Barnett MH, Williams DB, Day S, Macaskill P, McLeod JG. Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study. J Neurol Sci 2003; 213:1–6.
22. Wallin MT, Page WF, Kurtzke JF. Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann Neurol 2004; 55:65–71.
23. Grytten N, Glad SB, Aarseth JH, Nyland H, Midgard R, Myhr KM. A 50-year follow-up of the incidence of multiple sclerosis in Hordaland County, Norway. Neurology 2006; 66:182–186.
24. Voskuhl RR. Gender issues and multiple sclerosis. Curr Neurol Neurosci Rep 2002; 2:277–286.
25. Stordal E, Mykletun A, Dahl AA. The association between age and depression in the general population: a multivariate examination. Acta Psychiatr Scand 2003; 107:132–141.
26. Iacovides A, Andreoulakis E. Bipolar disorder and resembling special psychopathological manifestations in multiple sclerosis: a review. Curr Opin Psychiatry 2011; 24:336–340.
27. Feinstein A. The neuropsychiatry of multiple sclerosis. Can J Psychiatry 2004; 49:157–163.
28. Confavreux C, Compston DA, Hommes OR, McDonald WI, Thompson AJ. EDMUS, a European database for multiple sclerosis. J Neurol Neurosurg Psychiatry 1992; 55:671–676.
29. Feinstein A. Multiple sclerosis, disease modifying treatments and depression: a critical methodological review. Mult Scler 2000; 6:343–348.
30. Feinstein A. Neuropsychiatric syndromes associated with multiple sclerosis. J Neurol 2007; Suppl 2Suppl 2II73–II6.
31. Sarisoy G, Terzi M, Gümüş K, Pazvantoğlu O. Psychiatric symptoms in patients with multiple sclerosis. Gen Hosp Psychiatry 2013; 35:134–140.
32. Borazanci AP, Harris MK, Schwendimann RN, Gonzalez Toledo E, Maghzi AH, Etemadifar M, et al.. Multiple sclerosis: clinical features, pathophysiology, neuroimaging and future therapies. Future Neurol 2009; 4:229–246.
33. Caceres F, Vanotti S, Benedict RHB. RELACCEM Work Group. Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America: results of the RELACCEM study. Mult Scler Relat Disord 2014; 3:335–340.
34. Oppenheim H. Weitre notizen zur pathologie der disseminerten sklerose. Charite-ann 1889; 14:412–418.
35. Van Poppel H, Vereecken RL, Leruitte A. Neuro-muscular dysfunction of the lower urinary tract in multiple sclerosis. Paraplegia 1983; 21:374–379.
36. Gonor SE, Carroll DJ, Metcalfe JB. Vesical dysfunction in multiple sclerosis. Urology 1985; 25:429–431.
37. Awad SA, Gajewski JB, Sogbein SK, Murray TJ, Field CA. Relationship between neurological and urological status in patients with multiple sclerosis. J Urol 1984; 132:499–502.
38. Wingerchuk DM. Neuromyelitis optica. Adv Neurol 2009; 98:319–333.
39. Weinshenker BG, Wingerchuk DM, Vukusic S, Linbo L, Pittock SJ, Lucchinetti CF, et al.. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006; 59:566–569.
40. Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician 2004; 70:1935–1944.
41. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54–61.
42. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281:537–544.
43. Zorzon M, Zivadinov R, Bosco A, Bragadin LM, Moretti R, Bonfigli L, et al.. Sexual dysfunction in multiple sclerosis: a case–control study. I. Frequency and comparison of groups. Mult Scler 1999; 5:418–427.
44. Harrison AM, Bogosian A, Silber E, McCracken LM, Moss Morris R. ‘It feels like someone is hammering my feet’: understanding pain and its management from the perspective of people with multiple sclerosis. Mult Scler 2014[Epub ahead of print].
45. Minagar A, Sheremata WA. Glossopharyngeal neuralgia and MS. Neurology 2000; 54:1368–1370.
46. Voss WD, Arnett PA, Higginson CI, Randolph JJ, Campos MD, Dyck DG. Contributing factors to depressed mood in multiple sclerosis. Arch Clin Neuropsychol 2002; 17:103–115.
47. Rabins PV, Brooks BR, O’Donnell P, Pearlson GD, Moberg P, Jubelt B, et al.. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986; 109:585–597.
48. Brassington JC, Marsh NV. Neuropsychological aspects of multiple sclerosis. Neuropsychol Rev 1998; 8:43–77.
49. Krishnan KR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med 2005; 67:1–8.
50. Diaz Olavarrieta C, Cummings JL, Velazquez J, Garcia de la Cadena C. Neuropsychiatric manifestations of multiple sclerosis. J Neuropsychiatry Clin Neurosci 1999; 11:51–57.
51. Lynch SG, Kroencke DC, Denney DR. The relationship between disability and depression in multiple sclerosis: the role of uncertainty, coping and hope. Mult Scler 2001; 7:411–416.
52. Patten SB, Beck CA, Williams JV, Barbui C, Metz LM. Major depression in multiple sclerosis: a population-based perspective. Neurology 2003; 61:1524–1527.
53. Feinstein A, Magalhaes S, Richard JF, Audet B, Moore C. The link between multiple sclerosis and depression. Nat Rev Neurol 2014; 10:507–517.
54. Feinstein A, Roy P, Lobaugh N, Feinstein K, O’Connor P, Black S. Structural brain abnormalities in multiple sclerosis patients with major depression. Neurology 2004; 62:586–590.
55. Panitch HS, Thisted RA, Smith RA, Wynn DR, Wymer JP, Achiron A, et al.. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol 2006; 59:780–787.
56. Politte LC, Huffman JC, Stern TA. Neuropsychiatric manifestations of multiple sclerosis. Prim Care Companion J Clin Psychiatry 2008; 10:318–324.
57. Hurley RA, Taber KH, Zhang J, Hayman LA. Neuropsychiatric presentation of multiple sclerosis. J Neuropsychiatry Clin Neurosci 1999; 11:5–7.
58. Calabrese P. Neuropsychology of multiple sclerosis – an overview. J Neurol 2006; 253Suppl 1I10–I15.
59. Nocentini U, Pasqualetti P, Bonavita S, Buccafusca M, de Caro MF, Farina D, et al.. Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis. Mult Scler 2006; 12:77–87.
60. Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Mult Scler 2013; 19:1765–1772.
61. Patti F, Morra VB, Amato MP, Trojano M, Bastianello S, Tola MR, et al.. Subcutaneous interferon β-1a may protect against cognitive impairment in patients with relapsing-remitting multiple sclerosis: 5-year follow-up of the COGIMUS study. PLoS One 2013; 8:e74111.
62. Asghar Ali AA, Taber KH, Hurley RA, Hayman LA. Pure neuropsychiatric presentation of multiple sclerosis. Am J Psychiatry 2004; 161:226–231.
63. Pantano P, Mainero C, Caramia F. Functional brain reorganization in multiple sclerosis: evidence from fMRI studies. J Neuroimaging 2006; 16:104–114.
64. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613.
65. Amato MP, Bartolozzi ML, Zipoli V, Portaccio E, Mortilla M, Guidi L, et al.. Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment. Neurology 2004; 63:89–93.
66. Penny SA, Summers MM, Swanton JK, Cipolotti L, Miller DH, Ron MA. Changing associations between cognitive impairment and imaging in multiple sclerosis as the disease progresses. J Neuropsychiatry Clin Neurosci 2013; 25:134–140.
67. Messina S, Patti F. Gray matters in multiple sclerosis: cognitive impairment and structural MRI. Mult Scler Int 2014; 2014:609697.
68. Goodin DS. Magnetic resonance imaging as a surrogate outcome measure of disability in multiple sclerosis: Have we been overly harsh in our assessment? Ann Neurol 2006; 59:597–605.
69. Truyen L, van Waesberghe JH, van Walderveen MA, van Oosten BW, Polman CH, Hommes OR, et al.. Accumulation of hypointense lesions (‘black holes’) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996; 47:1469–1476.
70. Arnett PA, Rao SM, Bernardin L, Grafman J, Yetkin FZ, Lobeck L. Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis. Neurology 1994; 44pt 1420–425.
71. Foong J, Rozewicz L, Quaghebeur G, Davie CA, Kartsounis LD, Thompson AJ, et al.. Executive function in multiple sclerosis. The role of frontal lobe pathology. Brain 1997; 120Pt 115–26.
72. Rovaris M, Filippi M, Falautano M, Minicucci L, Rocca MA, Martinelli V, et al.. Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis. Neurology 1998; 50:1601–1608.
73. Miki Y, Grossman RI, Udupa JK, Wei L, Kolson DL, Mannon LJ, et al.. Isolated U-fiber involvement in MS: preliminary observations. Neurology 1998; 50:1301–1306.
74. Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos GP, Sternberg EM, et al.. Multiple sclerosis is associated with alterations in hypothalamic–pituitary–adrenal axis function. J Clin Endocrinol Metab 1994; 79:848–853.
75. Vattakatuchery JJ, Rickards H, Cavanna AE. Pathogenic mechanisms of depression in multiple sclerosis. J Neuropsychiatry Clin Neurosci 2011; 23:261–276.
76. Feinstein A. Depression associated with multiple sclerosis: an etiological conundrum. Can J Psychiatry 1995; 40:573–576.
77. Zorzon M, Zivadinov R, Nasuelli D, Ukmar M, Bratina A, Tommasi MA, et al.. Depressive symptoms and MRI changes in multiple sclerosis. Eur J Neurol 2002; 9:491–496.
78. Braun CMJ, Dumont M, Duval J, Hamel Hébert I, Godbout L. Brain modules of hallucination: an analysis of multiple patients with brain lesions. J Psychiatry Neurosci 2003; 28:432–449.
Keywords:

cognitive impairment; magnetic resonance imaging; multiple sclerosis; neuropsychiatric manifestations

© 2015 Institute of Psychiatry, Ain Shams University