INTRODUCTION

 

Multiple sclerosis is an autoimmune disease that ranks as a major cause of nervous system disability in young adults¹. Cognitive deficits in multiple sclerosis are known to be a common feature of the disease, up to 65% of patients are affected². Cognitive impairment may result from diffuse spread of microscopic pathology although lobar distribution of plaques can present with predominant deficit in corresponding cognitive function³. The severity of cognitive impairment correlates with total microscopic and macroscopic disease burden⁴. Cerebral atrophy may represent final cumulative effect of different types of multiple sclerosis induced lesions and serves as an important neurobiological marker of disease progression⁵.

Magnetic resonance imaging is a valuable tool for characterizing multiple sclerosis lesions and atrophy⁶.

Aim of the work: Was to study cognitive impairment in patients with multiple sclerosis and it’s relation to MRI findings.

 

PATIENTS AND METHODS

 

This study included 24 patients of both sexes with definite multiple sclerosis according to "McDonald's" criteria⁷ and its revision⁸ selected from Neurology Department of Menoufiya university hospital and 24 healthy persons selected from relatives of the patients as a control group matched for age, sex and level of education during the period between January 2008 - January 2009. Written consent was taken from the patients.

 

Exclusion criteria:

1.        A current or past history of medical or psychiatric disorder.

2.        Substance abuse.

3.        Neurological impairment that might interfere with psychometric testing.

4.        Multiple sclerosis relapse or corticosteroid use within the past six weeks.

 

All patients and control groups were subjected to the following:

1.        Full history taking, complete general and neurological examinations.

2.        Routine laboratory investigation.

3.        Neuropsychological tests: Stanford Binet “4th edition” battery. It is a neuropsychological battery designed by Binet and Semon at 1916, the “4th edition” published at 1986 and it was translated to Arabic by Lois and published at 1998. It is composed of 4 main tests which are: verbal reasoning, quantitative reasoning, visual reasoning and short term memory tests. The selected battery includes: Vocabulary test, comprehension test, pattern analysis test, bead memory test, sentence memory test and quantitative test that measure verbal, comprehension, memory, language and visuospatial functions.

4.        Magnetic Resonance Imaging of the brain (MRI): Brain MRI was performed using the following techniques: T1 weighted images, T2 weighted images and Fluid attenuated inversion recovery pulse sequences. The following data were determined: a) Lesion locations. B) Number of lesions. C) Cerebral atrophy parameters:

·          Third ventricle diameter.

·          Measurement of bicaudate ratio which is defined as the minimum intercaudate distance divided by the brain width along the same line.  

5.        Statistical analysis: Data were expressed as mean ± standard deviation (SD) or percentage. Comparison between data of the two groups was performed using unpaired t test, SPSS computer program (version 11) was used for data analysis. P value is considered highly significant if it was <0.001, significant if it was < 0.05. Correlation coefficient indicate the degree to which two measures are related. It ranges from -1 to +1, when =0 means no relationship.

 

RESULTS

 

a)            Clinical Results:

24 patients [9 males (37.5%) and 15 females (73.5%)[ with  definite multiple sclerosis according to McDonald's criteria were studied, their age was ranged from 19-40 years with mean age of 33.96±8.18 years. The mean age of the control group was 33.42±8.2 years and there was no statistically significant difference between both groups. According to the age of onset of the disease, 2 patients (8.33%) had onset between 11-20 years, 20 patients (88.33%) had onset between 21-30 years and 2 patients (8.33%) had onset between 31-40 years. Regarding the course of the disease, 20 patients were diagnosed as relapsing remitting (88.33%) and 4 patients (12.67%) were secondary progressive. Among multiple sclerosis patients, the number of the attacks ranged between 2-8 attacks with the mean 4.04±2.9 attacks and the disease duration ranged between 1-11 years with mean 5.38±3.16 years. Table (1) shows different clinical presentations of multiple sclerosis patients at the time of examination.

 

b)            Radiological Results:

Regarding site of the lesion, periventricular lesions were found in 21 patients (87.5%), brain stem lesions were found in 13 patients (54.1%) and cerebellar lesions were found in 9 patients (37.5%). Among 24 multiple sclerosis patients, 21 patients had increased third ventricular diameter, intercaudate distance and bicaudate ratio while 3 patients had normal parameters. Table (2) shows highly statistically significant difference between multiple sclerosis patients and control group (p<0.001) regarding the parameters of brain atrophy.

 

c)            Neuropsychological Results:

There was highly statistically significant difference between patients and control group in comprehension test, bead memory test, sentence memory, quantitative test and statistically significant in vocabulary test and pattern analysis test (Table 3).

There was negative correlation between disease duration and all results of Stanford Binet subtests, as the duration of the disease increased, there was more impairment in neuropsychological tests (Table 4).

The mean values of Stanford Binet tests were lower in patients with dilated third ventricle when compared to the corresponding values of patients with normal third ventricle diameter  (Table 5).

Also, the mean values of Stanford Binet tests were significantly lower in patients with increased bicaudate ratio when compared to corresponding values of patients with normal bicaudate ratio (Table 6).

 

Table 1. Clinical presentations among the patients group.

 

Clinical presentations	No of patients	%
Diminution of vision	5	20.83
Diplopia	10	41.66
Hemihypothesia	15	62.5
Weakness	12	50.00
Ataxia	9	37.5
Precipitancy	20	83.33
Impotence	3	12.5

Table 2. Comparison between patients and control groups regarding brain atrophy parameters.

 

MRI Findings	Patients (N=24) X±SD	Control (N=24) X±SD	t-test	P-value
3rd ventricle (mm)	2.5±0.84	1.9±0.27	3.33	< 0.001*
Intercaudate distance (mm)	8.99±0.52	6.15±0.38	26.68	<0.001*
Bicaudate ratio	0.14±0.04	0.09±0.03	5.09	<0.001*

* Significant at p<0.01

 

Table 3. Comparison between patients and control groups regarding Stanford Binet tests.

 

Stanford Binet Tests	Patients (N=24) X±SD	Control (N=24) X±SD	t-test	P-value
Vocabulary	47.83±15.76	56.26±4.57	2.51	< 0.05*
Comprehension	49.67±7.76	55.75±2.89	3.6	<0.001**
Pattern analysis	46.54±7.84	52.08±4.2	3.5	<0.05*
Bead memory	43.04±11.43	55.29±5.46	4.74	<0.001**
Sentence memory	46.25±11.89	56.38±3.23	4.02	<0.001**
Quantitative	39.29±11.62	52.96±5.6	5.19	<0.001**

* Significant at p<0.05 ** Significant at p<0.01

 

Table 4. Correlation between disease duration and Stanford Binet tests.

 

Stanford Binet Tests	Disease duration
	R	P
Vocabulary	-0.52	<0.05*
Comprehension	-0.62	<0.001**
Pattern analysis	-0.38	>0.05
Bead memory	-0.54	<0.05*
Sentence memory	-0.35	<0.05*
Quantitative	-0.44	<0.05*

* Significant at p<0.05 ** Significant at p<0.01

 

Table 5. Relation between the third ventricle diameter and results of Stanford Binet tests among patients group.

 

Stanford Binet Tests	Patients with normal 3rd ventricle (N=3) X±SD	Patients with dilated 3rd ventricle (N=21) X±SD	t-test	P-value
Vocabulary	55.33±0.58	43.28±9.78	2.09	<0.05*
Comprehension	51.64±1.03	46.18±3.54	2.61	<0.05*
Pattern analysis	49.21±1.24	44.19±2.27	3.7	<0.001**
Bead memory	53.74±0.89	45.95±8.42	2.12	<0.05*
Sentence  memory	55.08±1.23	43.65±8.42	2.3	<0.05*
Quantitative	49.87±2.31	37.12±92.27	2.31	<0.05*

* Statistical significant     ** Statistical high significant

 

Table 6. Relation between the bicaudate ratio and results of Stanford Binet tests among the patients group.

 

Stanford  Binet  Tests	Normal Bicaudate Ratio (N=3) X±SD	Increased Bicaudate Ratio (N=21) X±SD	t-test	P-value
Vocabulary	54.82±1.36	44.19±7.31	2.47	<0.05*
Comprehension	52.18±1.11	45.46±4.58	2.49	<0.05*
Pattern analysis	50.47±1.75	43.17±5.31	2.32	<0.05*
Bead memory	54.16±0.68	44.38±6.74	2.46	<0.05*
Sentence memory	55.62±0.96	42.72±7.94	2.76	<0.05*
Quantitative	49.39±2.97	38.78±9.27	1.93	>0.05

* Statistical significant    

DISCUSSION

 

Multiple sclerosis patients exhibit some neuropsychological dysfunction during the course of their disease⁴. The results of the present study revealed impaired cognitive functions in multiple sclerosis patients as measured by Stanford Binet tests. This  study revealed that, multiple sclerosis patients had significant memory impairment (verbal and visual)  and attention by using sentence memory test and bead memory (p<0.001) when compared to the results of the control group. In agreement with this study, Benedict et al.⁹, found significant impairment in verbal memory (p<0.001) by using California verbal learning test and Fletcher et al.¹⁰, who found that, the area of cognition typically impaired were memory and attention. Also, Piras et al.¹¹ found significant impairment of cognitive functions including verbal fluency, short and long term memory using verbal fluency and confrontational, naming test. On the contrast, Amato et al.¹² stated that, cognitive defects in verbal memory confirmed only on repeating the testing after 4-10 years.

Also, in this study, there was significant impairment in visuospatial perception (P<0.05) tested by pattern analysis test. This was in agreement with Bergendal et al.¹³ who found that, cognitive functions that is typically impaired are visuospatial skills. Also, Barak and Achion¹⁴ stated that, specific area of impairment included visual object recognition and both visual perception and discrimination. In this study, there was significant impairment in language among multiple sclerosis patients (P<0.05), this was in agreement with Karen et al.¹⁵, who found that, multiple sclerosis patients performed significantly lower than control on language based cognitive measures and Parameter et al.¹⁶, who found significant impairment in verbal fluency and language skills and this is explained by the prevalent left superotemporal hypoactivity on multiple sclerosis patients. Also, language impairment may be explained by impairment in other verbal cognitive functions¹⁵. Against these results, Amato et al.¹² found that, language functions have been considered to remain relatively intact among multiple sclerosis patients. The present study showed a negative correlation between the disease duration and the results of Stanford Binet tests. In agreement with these results, Amato, et al.³ found that, as the disease progress, the number of patients with cognitive defects tends to increase. Also, Karen et al.¹⁵ postulated that, as the disease progress, the profile of cognitive deficits tend to increase. On the other hand, Sperling et al.¹⁷ found that, the disease duration was not significantly related to baseline or follow up cognitive performance. The present study demonstrated brain atrophy in multiple sclerosis patients as measured by increased third ventricle diameter, increased intercaudate distance and bicaudate ratio when compared to the corresponding values in control group. In agreement with these results, Bakshi et al.¹⁸ found that, the third ventricular width was larger in patients group with multiple sclerosis than control group indicating central atrophy and Kallman et al.¹⁹ found significant third ventricular enlargement in multiple sclerosis patients that can be explained by axonal loss which is present in active inflammatory lesions during the course of multiple sclerosis. Bermel et al.²⁰ found that, bicaudate ratio was higher in patients with multiple sclerosis group than control group indicating subcortical atrophy, also Caon et al.²¹ stated that, bicaudate ratio increased in multiple sclerosis patients and it is a reliable measure of brain atrophy. This study showed that, patients with increased ventricular diameter and bicaudate ratio had significant impairment in the  tests of Stanford Binet. This was in agreement with Genova et al.²², who found that, enlargement of third ventricle in multiple sclerosis patients is an  indicator of impairment in broad range of cognitive functions.

Bendict et al.⁹ found that, patients with multiple sclerosis had larger ventricular diameter than the control persons  and the results of majority of neuropsychological tests significantly negatively correlated with the diameter of third ventricle. Berme et al.²⁰ concluded that, bicaudate ratio is increased in multiple sclerosis and is more closely associated with cognitive dysfunction. Deloire et al.²³ found that, increased bicaudate ratio showed a close relationship to cognitive dysfunction. Against, Sanchez et al.²⁴ results indicate that, third ventricular diameter and bicaudate ratio are not strong predictor of cognitive impairment in multiple sclerosis. Also, Catalaa et al.²⁵ found no strong correlation between MRI measures and neurocognitive functions.

 

Conclusion

Multiple sclerosis causes significant cognitive impairment among the patients and mainly affects the memory (verbal and visual), comprehension, attention, visuospatial perception, language and abstract reasoning and there was significant correlation between the MRI changes (dilatation of the third ventricle and increased bicaudate ratio) and the cognitive impairment occurs in the patients with multiple sclerosis.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.        Rosati G. The prevalence of multiple sclerosis in the world. An update. Neurol Sci., 2001; 22(2): 117-39.

2.        Achiron A, Barak Y. Cognitive impairment in probable multiple sclerosis. J Neurol Neurosurg Psychiatry. 2003; 74(4): 443-6.

3.        Amato MP, Zipoli V, Portaccio E. Multiple sclerosis related cognitive change: A review of cross sectional and longitudinal studies. J Neurol sci. 2006; 15: 245-2.

4.        Amato MP, Portaccio E, Goretti B, Zipoli V, Battaglini M, Bartolozzi ML, et al. Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. Arch Neurol. 2007; 64(8): 1157-61.

5.        Calabrese M, Filippi M, Rovaris M, Mattisi I, Bernard V, Atzori M, et al. Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study. Neurol Image. 2008; 42(4): 1324-8.  

6.        Ge Y, Law M, Johnson G, Zohrabian VM. Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis: characterizing haemodynamic impairment and inflammatory activity. Am J Neuroradiol. 2005; 26: 1539-47.

7.        McDonald WI, Compston A, EdanG, Goodkin O, Hartung HP, Lublin FD, Weinshenker B.Y. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001; 50(1): 121-7.

8.        Polman CH, Reingold SC, Edan G, Filippi M, Thompson A.J. Diagnostic criteria for multiple sclerosis: Revision to the "McDonald criteria. Ann Neurol. 2005; 58(6): 840-6.

9.        Benedict RH, Cox D, Thompson LL, Foley F, Weinstock GB, Munschauer F. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004; 10(6):675-8.

10.     Flechter S, Vardi J, Finkelstein Y, Pollak L. Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: An open-label prospective 1 year study. Med Assoc J. 2007; 9(6): 457-9.

11.     Piras MR, Magnano I, Canu ED, Paulus KS, Satta WM, Soddu A, et al. Longitudinal study of cognitive dysfunction in multiple sclerosis: Neuropsychological, neuroradiological, and neurophysiological findings. J Neurol Neurosurg Psychiatry. 2003; 74(7): 878-85.

12.     Amato MP, Ponziani G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: A reappraisal after 10 years. Arch Neurol. 2001; 58: 1602-6.

13.     Bergendal G, Fredrikson S, Almkvist O. Selective decline in information processing in subgroups of multiple sclerosis: An 8 years longitudinal study. Eur Neurol. 2007; 57(4): 193-202.

14.     Barak Y. Achiron, A. Cognitive Fatigue in multiple sclerosis: Findings  from  a two-wave screening project.  J Neurol Sci. 2006; 245: 73-6.

15.     Turpin KV, Carroll LJ, Cassidy JD, Hader WJ. Deterioration in the heath-related quality of life of persons with multiple sclerosis: The possible warning signs. Mult Scler. 2007;13(8):1038-45.

16.     Parmenter BA, Shucard JL, shucard DW. Information processing deficits in multiple sclerosis: A matter of complexity. J Int Neuropsychol Soc. 2007; 13(3): 417-23.

17.     Sperling RA, Guttmann CR, Hohol MJ, Warfield SK, Jakab M, Parente M, et al. cognitive function in multiple sclerosis: A longitudinal study. Arch Neurol. 2001; 58(1): 115-21.

18.     Bakshi R, Benedict RH, Bermel RA, Caruthers SD, Puli SR, Tjoa CW, et al. T2 hypointensity in the deep gray matter of patients with multiple sclerosis: A quantitative magnetic resonance imaging study. Arch Neurol. 2002; 59(1): 62-8.

19.     Kallmann BA, Sauer J, Schliesser M, Warmuth MM, Flachenecker P, Becker DG, et al. Determination of ventricular diameters in multiple sclerosis patients with transcranial sonography (TCS):A two year follow-up study. J Neurol. 2004; 251(1): 30-4.

20.     Bermel RA, Bakshi R, Tjoa C, Puli SR, Jacobs L. Bicaudate ratio as a magnetic resonance imaging marker of brain atrophy in multiple sclerosis. Arch Neurol. 2002; 59(2): 275-80.

21.     Caon C, zvartau HM, Ching W, Lisak R, Tselis A, Khan O. Intercaudate nucleus ratio as a linear measure of brain atrophy in multiple sclerosis. Neurology. 2003; 60(2): 323-5.

22.     Genova HM, Hillary FG, Wylie G, Rypma B, Deluca J. Examination of processing speed deficits in multiple sclerosis using functional magnetic resonance imaging. J Int Neuropsychol Soc. 2009; 15(3): 383-9.

23.     Deloire MS, Bonnet MC, Salort E, Arimone Y, Boudineau M, Petry G, et al. How to detect cognitive dysfunction at early stages of multiple sclerosis? Mult Scler. 2006; 12(4): 445-52.

24.     Sanchez MP, Nieto A, Barroso J, Martin V, Gernandez MA. Brain atrophy as a marker of cognitive impairment in mildly disabling relapsing-remitting multiple sclerosis. Eur J Neurol. 2008; 15(10): 1091-9.

25.     Catalaa I, Fulton JC, Zhang X, Udupa JK, Kolson D, Grossman M, Wei L, et al. MR imaging quantitation of gray matter involvement in multiple sclerosis and its correlation with disability measures and neuro cognitive testing. Am J Neuroradiol. 1999; 20(9): 1613-8.