Standardized Whole Brain Mapping of Tubers and Subepedymal Nodules in Tuberous Sclerosis Complex

Khanum Ridler PhD; John Suckling PhD; Nicholas Higgins FRCR; Patrick Bolton PhD, FRCPsych; Edward Bullmore PhD, MRCPsych

Disclosures

J Child Neurol. 2004;19(9):658-665.

Results

Almost all patients (23/25) had radiologic evidence of at least one classic central nervous system lesion. The mean tuber count was 13.04 (SD = 10.36; range = 0-36).

Whole brain tuber density mapping (Figure 1^[21]) demonstrated that tubers were widely but not uniformly distributed throughout the cerebral gray matter. Neocortical gray matter had the highest density of tubers; tuber density was relatively reduced in the cerebellum, medial temporal lobe, and subcortical nuclei.

(Enlarge Image)

Whole brain lesion density map showing the frequency of tubers (red and green color scale) and subependymal nodules (blue and purple color scale) in a group of 25 high-functioning adults with tuberous sclerosis complex. The lesion density map was developed by superimposing all of the subjects' lesion maps in the standard space. The left side of each panel represents the right side of the brain; the z-coordinate for each axial slice in the standard space of Talairach and Tournoux[21] is given in millimeters. The scale for tubers and white-matter abnormalities ranges from one subject having a lesion in the same voxel ( red ) to seven subjects (the maximum overlap) having a lesion in the same voxel ( green ). The scale for nodules ranges from one subject having a lesion in the same voxel ( blue ) to six subjects (the maximum overlap) having a lesion in the same voxel ( pink ).

Tuber frequency was quantified in each neocortical lobe, cingulate gyrus, and medial temporal lobe and the major subcortical structures (Figure 2). The highest frequency of tubers was in the frontal lobe, followed by the parietal, temporal, occipital, and cingulate cortices. Bilateral occurrence of tubers was frequent, especially in the frontal lobe. The high frequency of tubers in the cingulate gyrus was notable in the absence of any prior reports of cingulate tubers.

(Enlarge Image)

A, Tuber frequency for lobes and major subcortical structures. B, Tuber density for lobes and major subcortical structures. The error bars represent one standard error from the group mean. Frequency was given in the percentage of subjects with an affected lobe or major subcortical structure. Tuber density was measured by the average percentage of each lobe occupied by lesions across the group.

To account for different lobar sizes, we used the percentage occupancy of each lobe by tubers to estimate tuber density (Figure 2). This analysis revealed a slightly different rank order of lesion load in that the greatest percentage occupancy by tubers was found in the parietal lobe. We also estimated the percentage occupancy by tubers at a finer-grained level of anatomic resolution defined by sublobar regions corresponding approximately to major cortical gyri and subcortical nuclei (Figure 3^[24]). This showed that the inferior parietal lobule had the highest mean density of tubers (1.15% regional volume) and the angular gyrus had the maximum density of tubers (14.1% of regional volume was replaced by tubers in one individual).

(Enlarge Image)

A, Tuber density for cortical regions and major subcortical nuclei. B, Subependymal nodule density for cortical regions and major subcortical nuclei. These panels represent the density of lesions, which was measured as the average percentage occupancy of lesions for each region on each side of the brain, where regions were the Montreal Neurological Institute template regions.[24] The error bars represent one standard error from the mean. As expected, subependymal nodules encroached from the ventricles mainly into the caudate. The lobar and major subcortical structure groupings of these regional parcellations are presented across the bottom of the figure. Inf = inferior; Mid = middle; Orb = orbital; Sup = superior.

Repeated measures ANOVA of the regional tuber density data demonstrated a significant main effect of region ( F _(53,24) = 3.87; P = .001) but no significant effect of side (right versus left: F _(1,24) = 2.82; P = .11) and no significant interaction between region and side ( F _(1,53) = 0.98; P = .51).

Whole brain subependymal nodule density mapping (see Figure 1) demonstrated that nodules were concentrated in subcortical nuclei bilaterally. The caudothalamic sulcus in the walls of the lateral ventricles was the site of greatest nodule frequency; 56% of patients had one or more nodules in this region.

Nodule density was estimated for each sublobar cortical region and major subcortical nuclei (Figure 3). The highest density of nodules was in the caudate nucleus (the mean percentage occupancy by nodules was 1.45%); the maximum density of nodules was also located in the caudate nucleus (11.0% of caudate volume was occupied by nodule in one individual). Caudate nodules were almost always bilateral. The putamen, pallidum, thalamus, and olfactory and anterior cingulate cortices were the other sites of notable nodule density. The thalamus was frequently involved (48% of patients had one or more nodules in the thalamus), but the density of nodules in the thalamus was typically low (the mean percentage occupancy by nodules was 0.18%).

Repeated measures ANOVA of the regional nodule density data demonstrated a significant main effect of region ( F _(53,24) = 6.39; P < .001) but no significant effect of side (right versus left: F _(1,24) = 0.04; P = .85) and no significant interaction between region and side ( F _(1,53) = 0.09; P = .85).

There was a strong positive correlation between whole brain tuber volume and both whole brain white-matter lesion volume ( r = .962; P < .001) and whole brain subependymal nodule volume ( r = .760; P < .001) (Figure 4). There was also a significant positive correlation between whole brain subependymal nodule volume and whole brain white-matter lesion volume ( r = .813; P < .001).

(Enlarge Image)

Positive correlation between whole brain tuber and white-matter abnormality volume and whole brain subependymal nodule (SEN) volume in 25 high-functioning adults with tuberous sclerosis complex. r = .76; P < .001.

At a regional level of analysis, subependymal nodule volume in the basal ganglia was significantly positively correlated with tuber volume in frontal ( r = .639; P < .001), occipital ( r = .797; P < .001), temporal ( r = .715; P < .001), and parietal lobes ( r = .601; P < .001). Tuber volume in the frontal, occipital, and parietal lobes was also significantly positively correlated with subependymal nodule volume in the thalamus ( P < .05 for all correlations). However, there were no significant correlations between tuber volume in the cingulatecortex and subependymal nodule volume in the basal ganglia or thalamus.

Intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was not significantly correlated with whole brain tuber count, tuber volume, white-matter abnormality volume, or subependymal nodule volume ( P > .05 for all correlations).

When the sample was subdivided into those patients ( n = 9) who had never had an epileptic seizure and those patients ( n = 16) who had a lifetime history of at least one seizure, we found significantly greater whole brain tuber and associated white-matter abnormality volume in the patients with a history of epilepsy ( Table 2 ).

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Cite this: Standardized Whole Brain Mapping of Tubers and Subepedymal Nodules in Tuberous Sclerosis Complex - Medscape - Sep 01, 2004.

Prior Neuroimaging Studies of Frequency and Density of Tubers in Patients With Tuberous Sclerosis Complex
	Study
	Cusmai et al (1990)^[3]	Jambaque et al. (1991)^[4]	Webb et al. (1991)^[5]	Braffman et al (1992)^[1]	Shepherd et al. (1995)^[6]	Takanashi et al. (1995)^[7]	Bolton and Griffiths (1997)^[8]	Griffiths et al. (1998)^[9]	Baron and Barkovich (1999)^[10]	Seri et al. (1999)^[11]	Marti- Bonmati et al. (2000)^[12]	Weber et al. (2000)^[13]	Walz et al (2002)^[14]
Scan type	T₂	T₂	T₁	Short TR	T₁ and T₂	T₂ and FLAIR	12 MRI and 6 CT	T₁ and T₂	T₁ and T₂	FLAIR/T₁/T₂	T₁ and T₂	T₁ and T₂	T₂
N	34	23	11	42	75	5	18	20	7	14	34	29	50
Age mean	6	8	--	7.9	--	18	--	9	--	9	9	8	Pediatric
(range)	(0.5-18)	(3-16)	(5-60+)	(0.1-27)	(5-60+)	(13-25)	(3-23)	(2-17)	< 0.25	(7-10)	(2-14)	(0.5-26)
Subjects with lesion (%)
Tuber	94	96	82	95	100	100	89	95		100	94		92
SEN			64	95				100
WM				93				100	100
Bilateral lesion (%)
Tuber	76	65	73	92						86
SEN				85
WM				92
Average lesion number
Tuber	--	--	4	11.7	14.4	17.6	--	4.1	10.3	5.5	14.3	14.3	--
(range)		(0-8+)	(0-9)	(0-52)	(1-46)	(10-33)	(0-17)	(1-15)	(0-30)	(2-9)	(0-30)	(0-23)
SEN			2.1	6.4					13.7
(range)			(0-5)	(0-15)				(2-15+)	(6-24)
WM				6.1					35.7
(range)				(0-15)					(4-69)
Subjects with tuber in each lobe (%)
Frontal	91	43	64		81	100	67			93		60	92
Parietal	88	74	64		87	100				93		60	90
Occipital	--	65	36		27	80				43		50	64
Temporal	74	35	18		63	80	44			50		50	76
Cerebellar				12			22	15			44
Subjects with tuber in lobe bilaterally (%)
Frontal		50	43							23
Parietal		18	57							23
Occipital		40	25							17
Temporal		0	50							29
Total tuber number in group in each lobe (%)
Frontal			34	58		47	46		50
Parietal			41	27		24	18		26
Occipital			16	13		16	16		9
Temporal			7	4		14	15		15
Cerebellar				1			5

CT = computed tomography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; SEN = subependymal nodule; WM = white matter lesions.

This table represents a summary of studies of tuberous sclerosis complex that included tuber distribution information. Tuber distribution statistics were given in two forms: either as a percentage of subjects in the group or as a percentage of the tubers for the group. Once a tuber location was identified (by lobe), several studies also calculated the percentage of those subjects who had bilateral lesions within that lobe (rather than the percentage of the entire group).

Prior Neuroimaging Studies of Frequency and Density of Tubers in Patients With Tuberous Sclerosis Complex
	Study
	Cusmai et al (1990)^[3]	Jambaque et al. (1991)^[4]	Webb et al. (1991)^[5]	Braffman et al (1992)^[1]	Shepherd et al. (1995)^[6]	Takanashi et al. (1995)^[7]	Bolton and Griffiths (1997)^[8]	Griffiths et al. (1998)^[9]	Baron and Barkovich (1999)^[10]	Seri et al. (1999)^[11]	Marti- Bonmati et al. (2000)^[12]	Weber et al. (2000)^[13]	Walz et al (2002)^[14]
Scan type	T₂	T₂	T₁	Short TR	T₁ and T₂	T₂ and FLAIR	12 MRI and 6 CT	T₁ and T₂	T₁ and T₂	FLAIR/T₁/T₂	T₁ and T₂	T₁ and T₂	T₂
N	34	23	11	42	75	5	18	20	7	14	34	29	50
Age mean	6	8	--	7.9	--	18	--	9	--	9	9	8	Pediatric
(range)	(0.5-18)	(3-16)	(5-60+)	(0.1-27)	(5-60+)	(13-25)	(3-23)	(2-17)	< 0.25	(7-10)	(2-14)	(0.5-26)
Subjects with lesion (%)
Tuber	94	96	82	95	100	100	89	95		100	94		92
SEN			64	95				100
WM				93				100	100
Bilateral lesion (%)
Tuber	76	65	73	92						86
SEN				85
WM				92
Average lesion number
Tuber	--	--	4	11.7	14.4	17.6	--	4.1	10.3	5.5	14.3	14.3	--
(range)		(0-8+)	(0-9)	(0-52)	(1-46)	(10-33)	(0-17)	(1-15)	(0-30)	(2-9)	(0-30)	(0-23)
SEN			2.1	6.4					13.7
(range)			(0-5)	(0-15)				(2-15+)	(6-24)
WM				6.1					35.7
(range)				(0-15)					(4-69)
Subjects with tuber in each lobe (%)
Frontal	91	43	64		81	100	67			93		60	92
Parietal	88	74	64		87	100				93		60	90
Occipital	--	65	36		27	80				43		50	64
Temporal	74	35	18		63	80	44			50		50	76
Cerebellar				12			22	15			44
Subjects with tuber in lobe bilaterally (%)
Frontal		50	43							23
Parietal		18	57							23
Occipital		40	25							17
Temporal		0	50							29
Total tuber number in group in each lobe (%)
Frontal			34	58		47	46		50
Parietal			41	27		24	18		26
Occipital			16	13		16	16		9
Temporal			7	4		14	15		15
Cerebellar				1			5

Prior Neuroimaging Studies of Frequency and Density of Tubers in Patients With Tuberous Sclerosis Complex
	Study
	Cusmai et al (1990)^[3]	Jambaque et al. (1991)^[4]	Webb et al. (1991)^[5]	Braffman et al (1992)^[1]	Shepherd et al. (1995)^[6]	Takanashi et al. (1995)^[7]	Bolton and Griffiths (1997)^[8]	Griffiths et al. (1998)^[9]	Baron and Barkovich (1999)^[10]	Seri et al. (1999)^[11]	Marti- Bonmati et al. (2000)^[12]	Weber et al. (2000)^[13]	Walz et al (2002)^[14]
Scan type	T₂	T₂	T₁	Short TR	T₁ and T₂	T₂ and FLAIR	12 MRI and 6 CT	T₁ and T₂	T₁ and T₂	FLAIR/T₁/T₂	T₁ and T₂	T₁ and T₂	T₂
N	34	23	11	42	75	5	18	20	7	14	34	29	50
Age mean	6	8	--	7.9	--	18	--	9	--	9	9	8	Pediatric
(range)	(0.5-18)	(3-16)	(5-60+)	(0.1-27)	(5-60+)	(13-25)	(3-23)	(2-17)	< 0.25	(7-10)	(2-14)	(0.5-26)
Subjects with lesion (%)
Tuber	94	96	82	95	100	100	89	95		100	94		92
SEN			64	95				100
WM				93				100	100
Bilateral lesion (%)
Tuber	76	65	73	92						86
SEN				85
WM				92
Average lesion number
Tuber	--	--	4	11.7	14.4	17.6	--	4.1	10.3	5.5	14.3	14.3	--
(range)		(0-8+)	(0-9)	(0-52)	(1-46)	(10-33)	(0-17)	(1-15)	(0-30)	(2-9)	(0-30)	(0-23)
SEN			2.1	6.4					13.7
(range)			(0-5)	(0-15)				(2-15+)	(6-24)
WM				6.1					35.7
(range)				(0-15)					(4-69)
Subjects with tuber in each lobe (%)
Frontal	91	43	64		81	100	67			93		60	92
Parietal	88	74	64		87	100				93		60	90
Occipital	--	65	36		27	80				43		50	64
Temporal	74	35	18		63	80	44			50		50	76
Cerebellar				12			22	15			44
Subjects with tuber in lobe bilaterally (%)
Frontal		50	43							23
Parietal		18	57							23
Occipital		40	25							17
Temporal		0	50							29
Total tuber number in group in each lobe (%)
Frontal			34	58		47	46		50
Parietal			41	27		24	18		26
Occipital			16	13		16	16		9
Temporal			7	4		14	15		15
Cerebellar				1			5

Prior Neuroimaging Studies of Frequency and Density of Tubers in Patients With Tuberous Sclerosis Complex
	Study
	Cusmai et al (1990)^[3]	Jambaque et al. (1991)^[4]	Webb et al. (1991)^[5]	Braffman et al (1992)^[1]	Shepherd et al. (1995)^[6]	Takanashi et al. (1995)^[7]	Bolton and Griffiths (1997)^[8]	Griffiths et al. (1998)^[9]	Baron and Barkovich (1999)^[10]	Seri et al. (1999)^[11]	Marti- Bonmati et al. (2000)^[12]	Weber et al. (2000)^[13]	Walz et al (2002)^[14]
Scan type	T₂	T₂	T₁	Short TR	T₁ and T₂	T₂ and FLAIR	12 MRI and 6 CT	T₁ and T₂	T₁ and T₂	FLAIR/T₁/T₂	T₁ and T₂	T₁ and T₂	T₂
N	34	23	11	42	75	5	18	20	7	14	34	29	50
Age mean	6	8	--	7.9	--	18	--	9	--	9	9	8	Pediatric
(range)	(0.5-18)	(3-16)	(5-60+)	(0.1-27)	(5-60+)	(13-25)	(3-23)	(2-17)	< 0.25	(7-10)	(2-14)	(0.5-26)
Subjects with lesion (%)
Tuber	94	96	82	95	100	100	89	95		100	94		92
SEN			64	95				100
WM				93				100	100
Bilateral lesion (%)
Tuber	76	65	73	92						86
SEN				85
WM				92
Average lesion number
Tuber	--	--	4	11.7	14.4	17.6	--	4.1	10.3	5.5	14.3	14.3	--
(range)		(0-8+)	(0-9)	(0-52)	(1-46)	(10-33)	(0-17)	(1-15)	(0-30)	(2-9)	(0-30)	(0-23)
SEN			2.1	6.4					13.7
(range)			(0-5)	(0-15)				(2-15+)	(6-24)
WM				6.1					35.7
(range)				(0-15)					(4-69)
Subjects with tuber in each lobe (%)
Frontal	91	43	64		81	100	67			93		60	92
Parietal	88	74	64		87	100				93		60	90
Occipital	--	65	36		27	80				43		50	64
Temporal	74	35	18		63	80	44			50		50	76
Cerebellar				12			22	15			44
Subjects with tuber in lobe bilaterally (%)
Frontal		50	43							23
Parietal		18	57							23
Occipital		40	25							17
Temporal		0	50							29
Total tuber number in group in each lobe (%)
Frontal			34	58		47	46		50
Parietal			41	27		24	18		26
Occipital			16	13		16	16		9
Temporal			7	4		14	15		15
Cerebellar				1			5

Cognitive and Neuroimaging Differences Between Subgroups of Patients With Tuberous Sclerosis Complex Categorized According to Presence or Absence of a Lifetime History of Epilepsy
Measure	Seizure Free (n = 9)	Seizure Positive (n = 16)	t (df = 23)	P	Mean Difference	95% CI of Mean Difference
WASI IQ (SD)	121.67 (7.4)	114.19 (14)	-1.738	.096	-7.479	-16.38 1.43
SEN volume (SD)	0.23 (0.2)	0.89 (1.3)	2.033	.058	0.660	-0.026 1.35
Tuber count (SD)	10.28 (8.9)	13.78 (10.4)	0.888	.356	3.503	-4.76 11.76
Tuber and white-matter lesion volume (SD)	2.42 (1.6)	8.05 (7.0)	3.064	.007	5.628	1.76 9.49

SEN = subependymal nodule; WASI = Wechsler Abbreviated Scale of Intelligence.

Prior Neuroimaging Studies of Frequency and Density of Tubers in Patients With Tuberous Sclerosis Complex
	Study
	Cusmai et al (1990)^[3]	Jambaque et al. (1991)^[4]	Webb et al. (1991)^[5]	Braffman et al (1992)^[1]	Shepherd et al. (1995)^[6]	Takanashi et al. (1995)^[7]	Bolton and Griffiths (1997)^[8]	Griffiths et al. (1998)^[9]	Baron and Barkovich (1999)^[10]	Seri et al. (1999)^[11]	Marti- Bonmati et al. (2000)^[12]	Weber et al. (2000)^[13]	Walz et al (2002)^[14]
Scan type	T₂	T₂	T₁	Short TR	T₁ and T₂	T₂ and FLAIR	12 MRI and 6 CT	T₁ and T₂	T₁ and T₂	FLAIR/T₁/T₂	T₁ and T₂	T₁ and T₂	T₂
N	34	23	11	42	75	5	18	20	7	14	34	29	50
Age mean	6	8	--	7.9	--	18	--	9	--	9	9	8	Pediatric
(range)	(0.5-18)	(3-16)	(5-60+)	(0.1-27)	(5-60+)	(13-25)	(3-23)	(2-17)	< 0.25	(7-10)	(2-14)	(0.5-26)
Subjects with lesion (%)
Tuber	94	96	82	95	100	100	89	95		100	94		92
SEN			64	95				100
WM				93				100	100
Bilateral lesion (%)
Tuber	76	65	73	92						86
SEN				85
WM				92
Average lesion number
Tuber	--	--	4	11.7	14.4	17.6	--	4.1	10.3	5.5	14.3	14.3	--
(range)		(0-8+)	(0-9)	(0-52)	(1-46)	(10-33)	(0-17)	(1-15)	(0-30)	(2-9)	(0-30)	(0-23)
SEN			2.1	6.4					13.7
(range)			(0-5)	(0-15)				(2-15+)	(6-24)
WM				6.1					35.7
(range)				(0-15)					(4-69)
Subjects with tuber in each lobe (%)
Frontal	91	43	64		81	100	67			93		60	92
Parietal	88	74	64		87	100				93		60	90
Occipital	--	65	36		27	80				43		50	64
Temporal	74	35	18		63	80	44			50		50	76
Cerebellar				12			22	15			44
Subjects with tuber in lobe bilaterally (%)
Frontal		50	43							23
Parietal		18	57							23
Occipital		40	25							17
Temporal		0	50							29
Total tuber number in group in each lobe (%)
Frontal			34	58		47	46		50
Parietal			41	27		24	18		26
Occipital			16	13		16	16		9
Temporal			7	4		14	15		15
Cerebellar				1			5

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Standardized Whole Brain Mapping of Tubers and Subepedymal Nodules in Tuberous Sclerosis Complex

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