Thalamic Degeneration in X-ChromosomeLinked Copper Malabsorption Makoto Iwata, M D , Asao Hirano, M D , and Joseph H. French, M D
Thalamic degeneration was present in 5 autopsied cases of X-chromosome-linked copper malabsorption (X-cLCM), Menkes' kinky hair disease. Among the thalamic nuclei, those in the formatio paraventricularis, intralamellaris, and extralamellaris were spared. T h e nuclei projecting t o the granular cortices had severe neuronal depopulation. The thalamic nuclei that send axons to the agranular cortices were less often and less severely involved. T h e thalamic afferent system was intact except for degeneration of the red nucleus. Cerebral cortical lesions varied from case to case and usually were less marked than thalamic neuronal changes. Iwata M, Hirano A, French JH: Thalamic degeneration in X-chromosome-
linked copper malabsorption. Ann Neurol 5:359-366, 1979
Although Menkes et a1 [18] and others [I, 5,121 have reported thalamic degeneration in X-chromosomelinked copper malabsorption (X-cLCM), no systematic investigation of the thalamic degeneration in this disease has been reported. W e have examined 5 patients with this disease postmortem and have found severe degeneration in the thalamic nuclei in all 5. This communication details those results.
Materials and Methods Clinical details o n the 5 patients are shown in Table 1. Thc diagnosis of X-cLCM was conhrmed by the clinical manifestations [6], hypocupremia, hypoceruloplasminemia [GI, anti pathological findings in the cerebellum. The detailed pathological findings in Patient 4 have been reported previously [7]. The electron microscopic findings of Purkin je cells in Patients 2 and 5 have also been reported 191. I n every case, paraffin sections stained by hematoxylin and eosin, luxol fast bluelperiodic acid-Schiff, cresyl violet, Bielschowsky, Holzer, and phosphotungstic acidhematoxylin were examined under the light microscope. Celloidin sections stained by Woelcke and cresyl violet as well as frozen sections stained by Sudan IV and axonal silver impregnation were examined in some cases. Brain sections from 6 infants ranging in age from 6 to 20 months (brain weight, 650 to 1,210 gm) were similarly stained and examined; these served as controls. The nomenclature for the thalamic nuclei follows that of Dewulf [ 4 ] .
Results Thalamic Degeneration Thalamic alteration was profound in every case. T h e main lesion was neuron loss with fibrous gliosis and From the Division o f Neuropathology, Department of Pathology and Department of Pediatric Neurology, Montetiore Hospital and Medical Center, Bronx, NY.
pallor in the myelin preparations (Figs 1,2). T h e topographical distribution of the neuronal changes was almost identical in every case. Table 2 is a summary of the topographical distribution of the thalamic changes. The nuclei of the formatio intralamellaris and the formatio paraventricularis were well preserved in all cases (Fig 3A-C). In these nuclei the neuron cell bodies were spared. In addition, the surrounding neuropil was preserved and no glial reaction was present. T h e formatio extralamellaris was also fairly well preserved. In contrast, the nuclei of the formatio lateralis, such as the nucleus ventralis posterior, nucleus dorsalis anterior, nucleus dorsalis posterior, the formatio medialis, and the medial and lateral geniculate bodies constantly showed a very marked-nearly totalneuron loss and intense fibrous gliosis, with only a few small shrunken neurons remaining (Fig 3A-C). T h e formatio posterior (pulvinar) was similarly affected, but the degenerative changes were restricted to the lateral portion while the medial portion of the pulvinar was spared (Fig 3D). In addition to neuron depopulation, several calcospherites, positively stained by both von Kossa and iron stain, were noted in the degenerated portion of the pulvinar. T h e formatio anterior and the nucleus dorsalis superficialis were spared in 3 patients (Nos. 2, 3 , and 51, but slight neuron loss with mild glial proliferation was seen in Patients 1 and 4. T h e lesions in the nucleus ventralis anterior and nucleus ventralis oralis were less marked than those in other nuclei of the formatio lateralis, and many apparently normal neurons were noted. Address reprint rcquests to D r Iwata, Division o f Neuropatholohy. Department of Pathology. Montetiore Hospital and Med~cal Center, 11 1 E 210th St, Bronx, N Y 10467.
Accepted for publication Aug 28, 1978.
0364-5 134/79/04035')-08$01.25 @ 1978 by Asao Hirano
359
Table I. Clinical Dutu
ON
Patient Data Age at death (mo) Family history Parenteral copper theraPY Brain weight (gm) Autopsy findings
Thalamic degeneration Red nucleus degeneration Cerebral cortical lesion Pallor of the cerebral white matter
5 Autopsied Patients with X-Chromosonie-linked Copper hfalubsorption Patient 2
Patient 3
-
18 -
+a
+
+
+
-
-
+
650
700 Bilateral chronic subdural hematoma, bronchopneumonia, chronic cystitis
580
450
Bilateral chronic su bdural hematoma, bronchopneumonia
Bronchopneumonia, diverticulum of the urinary bladder
720 Bronchopneumonia
Patient 1 13
Bronchopneumonia, diverticulum of the urinary bladder
18
Patient 4 21
Patient 5 25 +a
++ ++
?
++ ++
++ ++
++ ++
5
+
+
+ +
++
++
+
+
+
+
"Siblings. - =
absent; ? = equivocal;
+
=
present;
++ = severe; ? = not examined.
FiR 1 . Coronul section of the thalamus (Patient 51 .rhoruing fibrnu.\ glioJis in the niicleris medialis (m). nudeus dorsalii posterior (dp). and nucleus i,entralis posterior (vp). The nurlei of-the forniatio intralumellaris (ila)..fornzatio parar,etitrlrrilarir (pv). and nucleus dor.sa1i.r siiperf;riali.r (dsf)ure spared. The lateral Keniciilate body (gl)shows moderate glin.si.s. (Hnlzer: ~6 hefore 15 reduction.)
360 Annals of Neurology
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F i g 2. Three-dimensionul representation of the right thalami.r shmoinR the plane of F i g w e 1 and thalaniic nuclei ini,olr,ement in kinky hair diiease. Cross-butcher/ niirlei are moderately t o sei erely affected iri kinky hair disease, .stippled n d e i are only minimally intotimed. and urnbite nucfei are spared. ( A = fnrniutin anterior: m = nucleus medialis: va = nucler~ri,entralij anterior: vo = nitdens i8entrali.r ora1i.r: vp = nucleus i,etitrafr.r posterior: da = nucleus dor.ru1i.r anterior; dp = nucleus dorsa1i.r po.sterior; dsf = nucletis dnrsalis .ciipetj5(iali.r:pul = nur1eu.c pulrinaris lateralis: pum = nuc1eu.c piili,inuri.r mediali.r: gl = nucleus geniciilatus latera1i.r; g m = nucleus geniculatiis n2ediali.c. I
Table 2 . Thalanric CharrRes i n 5 Autopsied Patients with X-Chrotiro.rome-liizk~dCopper Malab.torption
Region
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Formatio anterior Formatio paraventricularis Formatio medialis Formatio intralamellaris Formatio Lateralis Nucleus ventralis anterior Nucleus ventralis oralis Nucleus ventralis posterior Nucleus dorsalis anterior Nucleus dorsalis posterior Formatio posterior (pulvinar) Formacio extralamellaris Nucleus geniculatus lateralis Nucleus geniculatus medialis
+
-
-
+
-
-
-
2
-
+++
+++
+++
-
-
-
+ + +++ +++ +++
+ ++
+++
+++
-
++
- = not affected; examined.
+
= slight reduction
of the neurons;
5
+++
-
-
-
-
+++ +++
>
+++ +++
++ ++
+++ t++
++
-
+ + +++ +++ +++ +++
;i
i
+++ -
>
5
+ +++ +++ +++
+
r’
= moderate neuron loss;
Subcortical Thalamic Afferents The corpus striatum and globus pallidus showed no appreciable alteration. T h e red nucleus revealed almost complete neuron loss with severe astrocytic reaction in every instance (Fig 4). The neurons of the dentate nucleus and their fibers in the superior cerebellar peduncle were well preserved. The thalamopetal fiber tracts, such as the mammillothalamic tract, the fornix, and the medial and lateral lemnisci, were intact. The optic tract was spared in 4 patients, but Patient 5 showed axonal degeneration in the axial region. Cerebral Cortex and White Matter The cerebral white matter was diffusely pale compared with control specimens. T h e volume of the white matter was fairly well preserved except in Patient 5, in whom it was markedly diminished. Some fat-laden macrophages were noted around the small vessels in Patient 5. T h e internal capsule was well myelinated but very thin in each case. However, the cerebral peduncle was not diminished in size. The cerebral cortices included several different kinds of pathological processes. In every case, many cortical neurons, either pyramidal cells or granule cells (or both), were dark and shrunken like the “dark neurons” often seen in biopsy specimens. Focal cortical infarcts were also noted. In Patient 3 , the cortical areas of the frontal convexity underlying a chronic subdural hematoma showed severe spongy change associated with an extensive old infarct (Fig 5A). Scattered foci of old and recent laminar cortical necrosis were also noted in Patients 2, 3 , and 5, mainly along the cortical border zone areas. However, the
+++
>
+++ i
= nearly complete neuron loss; ?
=
nor
pyramidal cells of Ammon’s horn were relatively well preserved, and only Patient 3 showed neuron loss in Sommer’s sector. In addition to these lesions, which were apparently secondary to anoxic episodes, there was more diffuse cortical degeneration consisting of a decrease in the cortical neurons, frequently associated with macroscopic thinning of the cortical strip. The most severe lesion of this kind was seen in the oldest patient (No. 5 ) , who showed a nearly complete loss of granule cells in the striate cortex (Fig 5B) and the fascia dentata (Fig 5C). Other cortical areas in Patient 5 revealed a diffuse loss of cortical neurons with little predilection for specific cortical layers (Fig 5D). The cortical lesions in Patients 2, 3, and 4 were similar to but less marked than those in Patient 5. Only careful examination and comparison with the control sections could reveal either diffuse or focal reduction of the cortical neurons (Fig 5E). The granule cells in the fascia dentata of the hippocampus were moderately diminished in Patients 3 and 4. The cerebral cortex of the youngest patient (No. 1) was the least affected. The cortical neurons were only scarcely reduced in number, and glial stains did not reveal significant astrocytic reaction in the cortical strips. In spite of the apparently well preserved cortical neurons, the white matter was pale, especially in the temporoparietooccipital area. T h e silver impregnation method revealed welldeveloped apical dendrites in the remaining cortical pyramidal neurons in Patients 3 and 4 (Fig 5F). In addition to the degenerative changes in the cortical neurons, a developmental abnormality was also noted. A considerable number of elongated neurons
Iwata et al: Thalamus in Kinky Hair Disease
361
362 Annals of Neurology Vol 5
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F i g 4 . Neuron loss in the red nucleus (Patient 1 ) . RF = fasciculus retrojexus. ( H 6 E ; X 100.)
still in the process of migration were founl within the subcortical white matter in every instance. Discussion Menkes et a1 [ 181 pointed out that in X-cLCM, neuron loss was noted in the medial and lateral thalamic nuclei and the anterior and central nuclei were spared. Kopp et a1 [12] showed complete thalamic involvement except for the paraventricular nucleus. Our report confirms the constant involvement of the thalamus in this disease and describes an exact topography for the thalamic lesion. The thalamic nuclei that have no direct corticopetal fibers, such as the nuclei of the formatio intralamellaris, the formatio paraventricularis, and the formatio extralamellaris, were all spared. On the other hand, the thalamic nuclei that have direct thalamocortical projections were constantly affected. Among the latter, those which send their axons to the agranular cortices, such as the formatio anterior and nucleus dorsalis superficialis (to the limbic cortex), the nucleus ventralis anterior F i g 3 . Thalamic nuclei in Patient 5 . IA) Neuron loss in the nucleus medialis (m). The nuclei dorsalis super-rialis (dsf) and formatio intra1amelluri.r (ila) are presewed. (dp = nucleus dorsalis posterior.) (B) Depopulated nucleus ventralis posterior (vp) and presewed nucleus intralamellaris. (C) The nucleus medialis shows neuron loss while the formatio paraventricularis (pv) is intact. (D) The medial pulvinar (pum) Ji spared but the lateral pulvinar (pul) is severely depopulated. (Nissl-rresylviolet; A x13, 8-D x40.i
(to the premotor cortex), and the nucleus ventralis oralis (to the motor cortex), were much less severely affected. Recognition of the thalamic degeneration in XcLCM is important from at least two standpoints. The discrepancy between the mildness of the cerebral cortical lesion and the severity of myelin pallor in the cerebral white matter associated with neutral fat droplets led Vagn-Hansen et a1 12 11 to the hypothesis that kinky hair disease is a leukodystrophy. This discrepancy can instead be explained by severe thalamic neuronal degeneration, which causes a secondary degeneration of the thalamocortical fibers in the cerebral white matter without major influence on cortical neurons. Second, the progressive developmental disability, which is a cardinal clinical manifestation in X-cLCM, can also be explained by the profound thalamic neuronal loss. Martin [14, 151 regarded the neuron loss in the formatio medialis as a possible cause of dementia in Creutzfeldt-Jakob disease. Since the formatio medialis is almost completely depopulated in every X-cLCM thalamus, this lesion may contribute to the developmental disturbance of the disease. Several possibilities should be considered concerning the pathogenesis of the thalamic degeneration. The direct effect of anoxia on the thalamic nuclei is an obvious one. The thalamic nuclei, such as the nucleus medialis and nucleus ventralis oralis, are known to be vulnerable to anoxia [16]. According to Masini et a1 [ 171, the formatio centralis, formatio paraventricularis, and formatio anterior are spared in neonatal asphyxia, while the nuclei of the formatio medialis and formatio lateralis show severe neuron loss with status marmoratus. This distribution of
Iwata et al: Thalamus in Kinky Hair Disease
363
-
FiK 5 . Frontal lobe in Patient 3 . shouing a cortical infarct underlying the siibdrrra[ hematoma und pallor in the rnyelin. (Woelcke: x2 before 1 0 5 redidon.! ( B I Striute cortex i n Patient 5 , showing severe neuronal depopulation. ( H G E ; x40 before 25 % reduction.) IC) Ammon’s horn with granule cell depletion (Patient 5 ) . ( H G E ) ; ~ 3 before 0 25% reduction.) ID, Srrperior temporal Urus in Putient 5 , .thvwinR depopulution in the medialportion in contrust to the intact lateralportion. (Cresyl r,iolet; ~ 3 before 0 25 S i reduction.) IE! Apparently intact striate (left side) andparastriate (right side) corticeJ in Patient 4. (Cresyl i’iolet: ~ 4 before 0 5 % enlarKement.) ( F ! The frontul cortex in Patient 3 . shmcming wellderrloped apical dendrites. (Sib impregnation: x I00 before 5 C i e~fargement.)
364 Annals of Neurology
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thalamic changes is similar to that seen in X-cLCM. The role of arterial abnormalities in X-cLCM was also stressed by Danks et a1 [3J, who hypothesized that the central nervous system lesions may result from vascular insufficiency. Such severe anoxic damage of the thalamic nuclei with no alteration in the basal ganglia or hippocampus would be difficult to understand, however, and it therefore seems unlikely that anoxia is the main cause of the thalamic degeneration. Transneuronal anterograde degeneration of thalamic neurons due to a lesion of thalamopetal fibers is known to occur in humans, at least in some thalamic nuclei [ 2 ] . However, among the thalamic afferent neurons in X-cLCM, only the red nucleus showed a constant neuron loss. Optic tract degeneration was noted in only 1 patient (No. 5 ) , who showed less degeneration of the lateral geniculate body than Patients 2 and 4 , in whom the optic tract was intact. Degeneration of the red nucleus, which has never been described before in this disease, may be responsible for degeneration of the nucleus ventralis oralis. This is, however, only partially deafferentated, because the afferent fibers from the dentate nucleus through the superior cerebellar peduncle remained intact. An alternative explanation is that the degener-
ation of the red nucleus resulted from transsynaptic retrograde damage due to thalamic degeneration. Transneuronal retrograde degeneration of thalamic nuclei is still a debatable entity. Cortical ablation and focal vascular lesions of the cerebral cortex are not suitable materials for its study. In such material, direct retrograde degeneration due to the axonal damage of thalamic neurons is an important factor in producing thalamic degeneration. More selective cortical neuronal disorders such as Alzheimer disease may cause degenerative changes in thalamic neurons [ 191. Whether these constitute transneuronal retrograde degeneration o r primary thalamic degeneration has not been demonstrated clearly. In addition, the thalamic neuronal changes in the presenile dementias, such as Alzheimer disease, are not as severe as those seen in X-cLCM, although the difference in age of usual victims of the two conditions must be considered. Thus we cannot deny the possibility of transsynaptic retrograde degeneration, because transsynaptic degeneration is more easily produced in developing than in fully developed brain [ 2 ] . Two findings tend to rule out retrograde transsynaptic degeneration as the cause of the thalamic changes. First, the cortical lesions are less extensive than those in the thalamus. Severe cortical lesions were restricted to focal ischemic changes; diffuse cortical lesions showed little reduction in neurons. For example, Patient 1 demonstrated almost complete neuron loss in certain thalamic nuclei while the cerebral cortex had only a minimal loss of cortical neurons. The severity and topography of thalamic lesions were relatively constant in every patient, regardless of age. Cortical changes varied from case to case as a function of the patient’s age. It is reasonable to conclude that the thalamic degeneration is primary and at least some of the cortical neuronal degeneration may reflect transneuronal anterograde degeneration. Topographically selective thalamic involvement is reported in metabolic diseases such as lipidosis 1131, Lafora disease [8, 101, various degenerative disorders such as Huntington’s chorea [ 161, Werdnig-Hoffman disease [ 111, spinocerebellar degenerations 1161, and Creutzfeldt-Jakob disease [ 14, 161. The specific topographical pattern of the thalamic degeneration in X-cLCM is unique and different from that seen in the metabolic and degenerative disorders in which it is still not known whether the changes are primary or secondary. References 1 . Agular MJ, Chadwick DL, Okuyama K, et al: Kinky hair disease: I. Clinical and pathological features. J Neuropathol Exp Neurol 25:507-522, 1966
lwata et al: Thalamus in Kinky Hair Disease
365
2. Cowan WM: Antegrade and retrograde transneuronal degeneration in the central and peripheral nervous system, in Nauta WJH, Ebbeson SDE (eds): Contemporary Research Methods in Neuroanatomy. New York, Springer, 1970, pp 217-251 3. Danks DM, Campbell PE, Stevens BJ, et al: Menkes' kinky hair syndrome: an inherited defect in copper absorption with widespread effects. Pediatrics 50: 188-201, 1972 4. Dewulf A: Anatomy of the Normal Human Thalamus: Topometry and Standardized Nomenclature. Amsterdam, Elsevier, 1971 5 . Erdohazi M, Barnes ND, Robinson MJ, et al: Cerebral malformation associated with metabolic disorder: a report of 2 cases. Acta Neuropathol 36:315-325, 1976 6. French JH: X-chromosome linked copper malabsorption (X-cLCM), in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, in press 7. Ghatak NR, Hirano A, Poon TP, et al: Trichopoliodystrophy: 11. Pathological changes in skeletal muscle and nervous system. Arch Neurol 26:60-72, 1972 8. Girard PL, Escourolle R, Dumas M, et al: Maladie de Lafora: h propos d'un cas chez un sujet de race senegalaise. J Neurol Sci 25~507-527, 1975 9. Hirano A, Llena JF. French JH, et al: Fine structure of the cerebellar conex in Menkes kinky-hair disease: Xchromosome linked copper malabsorption. Arch Neurol 34:52-56, 1977 10. Iwata M Contribution i I'etude de la maladie d e Lafora. MPmoire pour le titre d'assistant Ctranger, Universite de Paris, 1973 11. Iwata M, Hirano A: A neuropathological study of WerdnigHoffmann disease. Neurol Med (Tokyo) 8:115-128, 1978 12. Kopp N, Tommasi M, Carrier H, et al: Neuropathologie de la trichopoliodystrophie (maladie de Menkes): une observation anatomo-clinique. Rev Neurol (Paris) 131:775-789, 1975
366 Annals of Neurology Vol 5 No 4 April 1979
13. Lemieux LH: The thalamic Datholorn of amaurotic familv idiocy: a contribution KO the cytology of the thalamus. J Neuropathol Exp Neurol 13:343-352, 1954 14. Manin JJ: Les lesions de la couche optique dans la maladie de Creurtfeldt-Jakob et les formes apparentees: etude topographique de treize cas. Acta Neuropathol Suppl 3:92-103, 1967 15. Manin JJ: Thalamic syndrome, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, 1969, vol 2, pp 469-496 16. Martin JJ: Contribution i 1'Ptude d e I'anatomie du thalamus et d e sa pathologie au cours des maladies dCgCnPratives dices abiotrophiques. Acta Neurol Belg 7O:S-211, 1970 17. Masini T, Ishino H , Manin JJ: Sur un Ptat marbrC i la predilection thalamique et localisation pseudosysdmatike: sa diffkrentiation h I'egard des dCgenCrescences primaires. Acta Neuropathol 9:357-362, 1967 18. MenkesJH. Alter M, Steigleder GK, et al: A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29:764-779, 1962 19. Simma K: Uber Thalamusveranderungen bei seniler Demenz und bei der alzheimenchen Krankheit. Monatsschr Psychiatr Neurol 122:156-178, 1951 20. Vagn-Hansen PU, Reske-Nielsen E, Christensen LH: Menkes' d i s e a s e a new leucodystrophy(?). A clinical and neuropathological review together with a new case. Acta Neuropathol 25:103-119, 1973 21. Van Buren JM, Barke RC: Variations and connections of the human thalamus. New York, Springer, 1972 22. Vuia 0, Heyer D: Neuropathologic aspects in Menkes' kinky hair disease (trichopoliodystrophy). Neuropediatrie 5:329339, 1976 1 .
Thalamic degeneration was present in 5 autopsied cases of X-chromosome-linked copper malabsorption (X-cLCM), Menkes' kinky hair disease. Among the thalamic nuclei, those in the formatio paraventricularis, intralamellaris, and extralamellaris were spared. T h e nuclei projecting t o the granular cortices had severe neuronal depopulation. The thalamic nuclei that send axons to the agranular cortices were less often and less severely involved. T h e thalamic afferent system was intact except for degeneration of the red nucleus. Cerebral cortical lesions varied from case to case and usually were less marked than thalamic neuronal changes. Iwata M, Hirano A, French JH: Thalamic degeneration in X-chromosome-
linked copper malabsorption. Ann Neurol 5:359-366, 1979
Although Menkes et a1 [18] and others [I, 5,121 have reported thalamic degeneration in X-chromosomelinked copper malabsorption (X-cLCM), no systematic investigation of the thalamic degeneration in this disease has been reported. W e have examined 5 patients with this disease postmortem and have found severe degeneration in the thalamic nuclei in all 5. This communication details those results.
Materials and Methods Clinical details o n the 5 patients are shown in Table 1. Thc diagnosis of X-cLCM was conhrmed by the clinical manifestations [6], hypocupremia, hypoceruloplasminemia [GI, anti pathological findings in the cerebellum. The detailed pathological findings in Patient 4 have been reported previously [7]. The electron microscopic findings of Purkin je cells in Patients 2 and 5 have also been reported 191. I n every case, paraffin sections stained by hematoxylin and eosin, luxol fast bluelperiodic acid-Schiff, cresyl violet, Bielschowsky, Holzer, and phosphotungstic acidhematoxylin were examined under the light microscope. Celloidin sections stained by Woelcke and cresyl violet as well as frozen sections stained by Sudan IV and axonal silver impregnation were examined in some cases. Brain sections from 6 infants ranging in age from 6 to 20 months (brain weight, 650 to 1,210 gm) were similarly stained and examined; these served as controls. The nomenclature for the thalamic nuclei follows that of Dewulf [ 4 ] .
Results Thalamic Degeneration Thalamic alteration was profound in every case. T h e main lesion was neuron loss with fibrous gliosis and From the Division o f Neuropathology, Department of Pathology and Department of Pediatric Neurology, Montetiore Hospital and Medical Center, Bronx, NY.
pallor in the myelin preparations (Figs 1,2). T h e topographical distribution of the neuronal changes was almost identical in every case. Table 2 is a summary of the topographical distribution of the thalamic changes. The nuclei of the formatio intralamellaris and the formatio paraventricularis were well preserved in all cases (Fig 3A-C). In these nuclei the neuron cell bodies were spared. In addition, the surrounding neuropil was preserved and no glial reaction was present. T h e formatio extralamellaris was also fairly well preserved. In contrast, the nuclei of the formatio lateralis, such as the nucleus ventralis posterior, nucleus dorsalis anterior, nucleus dorsalis posterior, the formatio medialis, and the medial and lateral geniculate bodies constantly showed a very marked-nearly totalneuron loss and intense fibrous gliosis, with only a few small shrunken neurons remaining (Fig 3A-C). T h e formatio posterior (pulvinar) was similarly affected, but the degenerative changes were restricted to the lateral portion while the medial portion of the pulvinar was spared (Fig 3D). In addition to neuron depopulation, several calcospherites, positively stained by both von Kossa and iron stain, were noted in the degenerated portion of the pulvinar. T h e formatio anterior and the nucleus dorsalis superficialis were spared in 3 patients (Nos. 2, 3 , and 51, but slight neuron loss with mild glial proliferation was seen in Patients 1 and 4. T h e lesions in the nucleus ventralis anterior and nucleus ventralis oralis were less marked than those in other nuclei of the formatio lateralis, and many apparently normal neurons were noted. Address reprint rcquests to D r Iwata, Division o f Neuropatholohy. Department of Pathology. Montetiore Hospital and Med~cal Center, 11 1 E 210th St, Bronx, N Y 10467.
Accepted for publication Aug 28, 1978.
0364-5 134/79/04035')-08$01.25 @ 1978 by Asao Hirano
359
Table I. Clinical Dutu
ON
Patient Data Age at death (mo) Family history Parenteral copper theraPY Brain weight (gm) Autopsy findings
Thalamic degeneration Red nucleus degeneration Cerebral cortical lesion Pallor of the cerebral white matter
5 Autopsied Patients with X-Chromosonie-linked Copper hfalubsorption Patient 2
Patient 3
-
18 -
+a
+
+
+
-
-
+
650
700 Bilateral chronic subdural hematoma, bronchopneumonia, chronic cystitis
580
450
Bilateral chronic su bdural hematoma, bronchopneumonia
Bronchopneumonia, diverticulum of the urinary bladder
720 Bronchopneumonia
Patient 1 13
Bronchopneumonia, diverticulum of the urinary bladder
18
Patient 4 21
Patient 5 25 +a
++ ++
?
++ ++
++ ++
++ ++
5
+
+
+ +
++
++
+
+
+
+
"Siblings. - =
absent; ? = equivocal;
+
=
present;
++ = severe; ? = not examined.
FiR 1 . Coronul section of the thalamus (Patient 51 .rhoruing fibrnu.\ glioJis in the niicleris medialis (m). nudeus dorsalii posterior (dp). and nucleus i,entralis posterior (vp). The nurlei of-the forniatio intralumellaris (ila)..fornzatio parar,etitrlrrilarir (pv). and nucleus dor.sa1i.r siiperf;riali.r (dsf)ure spared. The lateral Keniciilate body (gl)shows moderate glin.si.s. (Hnlzer: ~6 hefore 15 reduction.)
360 Annals of Neurology
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April 1979
F i g 2. Three-dimensionul representation of the right thalami.r shmoinR the plane of F i g w e 1 and thalaniic nuclei ini,olr,ement in kinky hair diiease. Cross-butcher/ niirlei are moderately t o sei erely affected iri kinky hair disease, .stippled n d e i are only minimally intotimed. and urnbite nucfei are spared. ( A = fnrniutin anterior: m = nucleus medialis: va = nucler~ri,entralij anterior: vo = nitdens i8entrali.r ora1i.r: vp = nucleus i,etitrafr.r posterior: da = nucleus dor.ru1i.r anterior; dp = nucleus dorsa1i.r po.sterior; dsf = nucletis dnrsalis .ciipetj5(iali.r:pul = nur1eu.c pulrinaris lateralis: pum = nuc1eu.c piili,inuri.r mediali.r: gl = nucleus geniciilatus latera1i.r; g m = nucleus geniculatiis n2ediali.c. I
Table 2 . Thalanric CharrRes i n 5 Autopsied Patients with X-Chrotiro.rome-liizk~dCopper Malab.torption
Region
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Formatio anterior Formatio paraventricularis Formatio medialis Formatio intralamellaris Formatio Lateralis Nucleus ventralis anterior Nucleus ventralis oralis Nucleus ventralis posterior Nucleus dorsalis anterior Nucleus dorsalis posterior Formatio posterior (pulvinar) Formacio extralamellaris Nucleus geniculatus lateralis Nucleus geniculatus medialis
+
-
-
+
-
-
-
2
-
+++
+++
+++
-
-
-
+ + +++ +++ +++
+ ++
+++
+++
-
++
- = not affected; examined.
+
= slight reduction
of the neurons;
5
+++
-
-
-
-
+++ +++
>
+++ +++
++ ++
+++ t++
++
-
+ + +++ +++ +++ +++
;i
i
+++ -
>
5
+ +++ +++ +++
+
r’
= moderate neuron loss;
Subcortical Thalamic Afferents The corpus striatum and globus pallidus showed no appreciable alteration. T h e red nucleus revealed almost complete neuron loss with severe astrocytic reaction in every instance (Fig 4). The neurons of the dentate nucleus and their fibers in the superior cerebellar peduncle were well preserved. The thalamopetal fiber tracts, such as the mammillothalamic tract, the fornix, and the medial and lateral lemnisci, were intact. The optic tract was spared in 4 patients, but Patient 5 showed axonal degeneration in the axial region. Cerebral Cortex and White Matter The cerebral white matter was diffusely pale compared with control specimens. T h e volume of the white matter was fairly well preserved except in Patient 5, in whom it was markedly diminished. Some fat-laden macrophages were noted around the small vessels in Patient 5. T h e internal capsule was well myelinated but very thin in each case. However, the cerebral peduncle was not diminished in size. The cerebral cortices included several different kinds of pathological processes. In every case, many cortical neurons, either pyramidal cells or granule cells (or both), were dark and shrunken like the “dark neurons” often seen in biopsy specimens. Focal cortical infarcts were also noted. In Patient 3 , the cortical areas of the frontal convexity underlying a chronic subdural hematoma showed severe spongy change associated with an extensive old infarct (Fig 5A). Scattered foci of old and recent laminar cortical necrosis were also noted in Patients 2, 3 , and 5, mainly along the cortical border zone areas. However, the
+++
>
+++ i
= nearly complete neuron loss; ?
=
nor
pyramidal cells of Ammon’s horn were relatively well preserved, and only Patient 3 showed neuron loss in Sommer’s sector. In addition to these lesions, which were apparently secondary to anoxic episodes, there was more diffuse cortical degeneration consisting of a decrease in the cortical neurons, frequently associated with macroscopic thinning of the cortical strip. The most severe lesion of this kind was seen in the oldest patient (No. 5 ) , who showed a nearly complete loss of granule cells in the striate cortex (Fig 5B) and the fascia dentata (Fig 5C). Other cortical areas in Patient 5 revealed a diffuse loss of cortical neurons with little predilection for specific cortical layers (Fig 5D). The cortical lesions in Patients 2, 3, and 4 were similar to but less marked than those in Patient 5. Only careful examination and comparison with the control sections could reveal either diffuse or focal reduction of the cortical neurons (Fig 5E). The granule cells in the fascia dentata of the hippocampus were moderately diminished in Patients 3 and 4. The cerebral cortex of the youngest patient (No. 1) was the least affected. The cortical neurons were only scarcely reduced in number, and glial stains did not reveal significant astrocytic reaction in the cortical strips. In spite of the apparently well preserved cortical neurons, the white matter was pale, especially in the temporoparietooccipital area. T h e silver impregnation method revealed welldeveloped apical dendrites in the remaining cortical pyramidal neurons in Patients 3 and 4 (Fig 5F). In addition to the degenerative changes in the cortical neurons, a developmental abnormality was also noted. A considerable number of elongated neurons
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F i g 4 . Neuron loss in the red nucleus (Patient 1 ) . RF = fasciculus retrojexus. ( H 6 E ; X 100.)
still in the process of migration were founl within the subcortical white matter in every instance. Discussion Menkes et a1 [ 181 pointed out that in X-cLCM, neuron loss was noted in the medial and lateral thalamic nuclei and the anterior and central nuclei were spared. Kopp et a1 [12] showed complete thalamic involvement except for the paraventricular nucleus. Our report confirms the constant involvement of the thalamus in this disease and describes an exact topography for the thalamic lesion. The thalamic nuclei that have no direct corticopetal fibers, such as the nuclei of the formatio intralamellaris, the formatio paraventricularis, and the formatio extralamellaris, were all spared. On the other hand, the thalamic nuclei that have direct thalamocortical projections were constantly affected. Among the latter, those which send their axons to the agranular cortices, such as the formatio anterior and nucleus dorsalis superficialis (to the limbic cortex), the nucleus ventralis anterior F i g 3 . Thalamic nuclei in Patient 5 . IA) Neuron loss in the nucleus medialis (m). The nuclei dorsalis super-rialis (dsf) and formatio intra1amelluri.r (ila) are presewed. (dp = nucleus dorsalis posterior.) (B) Depopulated nucleus ventralis posterior (vp) and presewed nucleus intralamellaris. (C) The nucleus medialis shows neuron loss while the formatio paraventricularis (pv) is intact. (D) The medial pulvinar (pum) Ji spared but the lateral pulvinar (pul) is severely depopulated. (Nissl-rresylviolet; A x13, 8-D x40.i
(to the premotor cortex), and the nucleus ventralis oralis (to the motor cortex), were much less severely affected. Recognition of the thalamic degeneration in XcLCM is important from at least two standpoints. The discrepancy between the mildness of the cerebral cortical lesion and the severity of myelin pallor in the cerebral white matter associated with neutral fat droplets led Vagn-Hansen et a1 12 11 to the hypothesis that kinky hair disease is a leukodystrophy. This discrepancy can instead be explained by severe thalamic neuronal degeneration, which causes a secondary degeneration of the thalamocortical fibers in the cerebral white matter without major influence on cortical neurons. Second, the progressive developmental disability, which is a cardinal clinical manifestation in X-cLCM, can also be explained by the profound thalamic neuronal loss. Martin [14, 151 regarded the neuron loss in the formatio medialis as a possible cause of dementia in Creutzfeldt-Jakob disease. Since the formatio medialis is almost completely depopulated in every X-cLCM thalamus, this lesion may contribute to the developmental disturbance of the disease. Several possibilities should be considered concerning the pathogenesis of the thalamic degeneration. The direct effect of anoxia on the thalamic nuclei is an obvious one. The thalamic nuclei, such as the nucleus medialis and nucleus ventralis oralis, are known to be vulnerable to anoxia [16]. According to Masini et a1 [ 171, the formatio centralis, formatio paraventricularis, and formatio anterior are spared in neonatal asphyxia, while the nuclei of the formatio medialis and formatio lateralis show severe neuron loss with status marmoratus. This distribution of
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FiK 5 . Frontal lobe in Patient 3 . shouing a cortical infarct underlying the siibdrrra[ hematoma und pallor in the rnyelin. (Woelcke: x2 before 1 0 5 redidon.! ( B I Striute cortex i n Patient 5 , showing severe neuronal depopulation. ( H G E ; x40 before 25 % reduction.) IC) Ammon’s horn with granule cell depletion (Patient 5 ) . ( H G E ) ; ~ 3 before 0 25% reduction.) ID, Srrperior temporal Urus in Putient 5 , .thvwinR depopulution in the medialportion in contrust to the intact lateralportion. (Cresyl r,iolet; ~ 3 before 0 25 S i reduction.) IE! Apparently intact striate (left side) andparastriate (right side) corticeJ in Patient 4. (Cresyl i’iolet: ~ 4 before 0 5 % enlarKement.) ( F ! The frontul cortex in Patient 3 . shmcming wellderrloped apical dendrites. (Sib impregnation: x I00 before 5 C i e~fargement.)
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thalamic changes is similar to that seen in X-cLCM. The role of arterial abnormalities in X-cLCM was also stressed by Danks et a1 [3J, who hypothesized that the central nervous system lesions may result from vascular insufficiency. Such severe anoxic damage of the thalamic nuclei with no alteration in the basal ganglia or hippocampus would be difficult to understand, however, and it therefore seems unlikely that anoxia is the main cause of the thalamic degeneration. Transneuronal anterograde degeneration of thalamic neurons due to a lesion of thalamopetal fibers is known to occur in humans, at least in some thalamic nuclei [ 2 ] . However, among the thalamic afferent neurons in X-cLCM, only the red nucleus showed a constant neuron loss. Optic tract degeneration was noted in only 1 patient (No. 5 ) , who showed less degeneration of the lateral geniculate body than Patients 2 and 4 , in whom the optic tract was intact. Degeneration of the red nucleus, which has never been described before in this disease, may be responsible for degeneration of the nucleus ventralis oralis. This is, however, only partially deafferentated, because the afferent fibers from the dentate nucleus through the superior cerebellar peduncle remained intact. An alternative explanation is that the degener-
ation of the red nucleus resulted from transsynaptic retrograde damage due to thalamic degeneration. Transneuronal retrograde degeneration of thalamic nuclei is still a debatable entity. Cortical ablation and focal vascular lesions of the cerebral cortex are not suitable materials for its study. In such material, direct retrograde degeneration due to the axonal damage of thalamic neurons is an important factor in producing thalamic degeneration. More selective cortical neuronal disorders such as Alzheimer disease may cause degenerative changes in thalamic neurons [ 191. Whether these constitute transneuronal retrograde degeneration o r primary thalamic degeneration has not been demonstrated clearly. In addition, the thalamic neuronal changes in the presenile dementias, such as Alzheimer disease, are not as severe as those seen in X-cLCM, although the difference in age of usual victims of the two conditions must be considered. Thus we cannot deny the possibility of transsynaptic retrograde degeneration, because transsynaptic degeneration is more easily produced in developing than in fully developed brain [ 2 ] . Two findings tend to rule out retrograde transsynaptic degeneration as the cause of the thalamic changes. First, the cortical lesions are less extensive than those in the thalamus. Severe cortical lesions were restricted to focal ischemic changes; diffuse cortical lesions showed little reduction in neurons. For example, Patient 1 demonstrated almost complete neuron loss in certain thalamic nuclei while the cerebral cortex had only a minimal loss of cortical neurons. The severity and topography of thalamic lesions were relatively constant in every patient, regardless of age. Cortical changes varied from case to case as a function of the patient’s age. It is reasonable to conclude that the thalamic degeneration is primary and at least some of the cortical neuronal degeneration may reflect transneuronal anterograde degeneration. Topographically selective thalamic involvement is reported in metabolic diseases such as lipidosis 1131, Lafora disease [8, 101, various degenerative disorders such as Huntington’s chorea [ 161, Werdnig-Hoffman disease [ 111, spinocerebellar degenerations 1161, and Creutzfeldt-Jakob disease [ 14, 161. The specific topographical pattern of the thalamic degeneration in X-cLCM is unique and different from that seen in the metabolic and degenerative disorders in which it is still not known whether the changes are primary or secondary. References 1 . Agular MJ, Chadwick DL, Okuyama K, et al: Kinky hair disease: I. Clinical and pathological features. J Neuropathol Exp Neurol 25:507-522, 1966
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2. Cowan WM: Antegrade and retrograde transneuronal degeneration in the central and peripheral nervous system, in Nauta WJH, Ebbeson SDE (eds): Contemporary Research Methods in Neuroanatomy. New York, Springer, 1970, pp 217-251 3. Danks DM, Campbell PE, Stevens BJ, et al: Menkes' kinky hair syndrome: an inherited defect in copper absorption with widespread effects. Pediatrics 50: 188-201, 1972 4. Dewulf A: Anatomy of the Normal Human Thalamus: Topometry and Standardized Nomenclature. Amsterdam, Elsevier, 1971 5 . Erdohazi M, Barnes ND, Robinson MJ, et al: Cerebral malformation associated with metabolic disorder: a report of 2 cases. Acta Neuropathol 36:315-325, 1976 6. French JH: X-chromosome linked copper malabsorption (X-cLCM), in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, in press 7. Ghatak NR, Hirano A, Poon TP, et al: Trichopoliodystrophy: 11. Pathological changes in skeletal muscle and nervous system. Arch Neurol 26:60-72, 1972 8. Girard PL, Escourolle R, Dumas M, et al: Maladie de Lafora: h propos d'un cas chez un sujet de race senegalaise. J Neurol Sci 25~507-527, 1975 9. Hirano A, Llena JF. French JH, et al: Fine structure of the cerebellar conex in Menkes kinky-hair disease: Xchromosome linked copper malabsorption. Arch Neurol 34:52-56, 1977 10. Iwata M Contribution i I'etude de la maladie d e Lafora. MPmoire pour le titre d'assistant Ctranger, Universite de Paris, 1973 11. Iwata M, Hirano A: A neuropathological study of WerdnigHoffmann disease. Neurol Med (Tokyo) 8:115-128, 1978 12. Kopp N, Tommasi M, Carrier H, et al: Neuropathologie de la trichopoliodystrophie (maladie de Menkes): une observation anatomo-clinique. Rev Neurol (Paris) 131:775-789, 1975
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13. Lemieux LH: The thalamic Datholorn of amaurotic familv idiocy: a contribution KO the cytology of the thalamus. J Neuropathol Exp Neurol 13:343-352, 1954 14. Manin JJ: Les lesions de la couche optique dans la maladie de Creurtfeldt-Jakob et les formes apparentees: etude topographique de treize cas. Acta Neuropathol Suppl 3:92-103, 1967 15. Manin JJ: Thalamic syndrome, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, 1969, vol 2, pp 469-496 16. Martin JJ: Contribution i 1'Ptude d e I'anatomie du thalamus et d e sa pathologie au cours des maladies dCgCnPratives dices abiotrophiques. Acta Neurol Belg 7O:S-211, 1970 17. Masini T, Ishino H , Manin JJ: Sur un Ptat marbrC i la predilection thalamique et localisation pseudosysdmatike: sa diffkrentiation h I'egard des dCgenCrescences primaires. Acta Neuropathol 9:357-362, 1967 18. MenkesJH. Alter M, Steigleder GK, et al: A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29:764-779, 1962 19. Simma K: Uber Thalamusveranderungen bei seniler Demenz und bei der alzheimenchen Krankheit. Monatsschr Psychiatr Neurol 122:156-178, 1951 20. Vagn-Hansen PU, Reske-Nielsen E, Christensen LH: Menkes' d i s e a s e a new leucodystrophy(?). A clinical and neuropathological review together with a new case. Acta Neuropathol 25:103-119, 1973 21. Van Buren JM, Barke RC: Variations and connections of the human thalamus. New York, Springer, 1972 22. Vuia 0, Heyer D: Neuropathologic aspects in Menkes' kinky hair disease (trichopoliodystrophy). Neuropediatrie 5:329339, 1976 1 .
