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A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies
Clinical Neurology and Neurosurgery 104 (2002) 98 – 102 www.elsevier.com/locate/clineuro
A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies Shin Fujimoto a, Toshihide Kumamoto a,*, Tomoko Ito a, Kunihiro Sannomiya a, Takashi Inuzuka b, Tomiyasu Tsuda a a
Third Department of Internal Medicine, Oita Medical Uni6ersity, Hasama 1 -1, Oita 879 -5593, Japan b Department of Gerontology, Gifu Uni6ersity School of Medicine, Gifu, Japan
Received 2 February 2001; received in revised form 6 September 2001; accepted 23 November 2001
Abstract Only a few cases of paraneoplastic neurologic syndrome with multiple cranial palsies have been reported. This is the case report of a patient with small-cell lung cancer and a high titer of anti-Hu antibodies who developed a tonic left pupil and multiple cranial nerve palsies, including palsies of the left fifth through tenth nerves and both twelfth nerves, as in Garcin syndrome showing at least more than seven ipsilateral cranial nerve palsies, in the course of paraneoplastic sensory neuronopathy (PSN). Pathologic examination revealed no metastasis or direct invasion of malignancy with gliosis and perivascular inflammation throughout the brainstem, indicating paraneoplastic encephalomyelitis (PEM). The numbers of EBM11 + cells (probably reactive microglia), CD8+ cells, and CD4 + cells increased. Intracellular adhesion molecule-1 and lymphocyte function associated molecule-1 were expressed intensely on the endothelia of microvessels and were found to have infiltrated mononuclear cells around microvessels in the brainstem. Multiple cranial nerve palsies and their effects including the tonic pupil are likely due to the paraneoplastic effect of the primary systemic malignancy. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Paraneoplastic syndrome; Paraneoplastic encephalomyelitis; Paraneoplastic sensory neuronopathy; Multiple cranial nerve palsies; Tonic pupil; Adhesion molecules
1. Introduction Paraneoplastic encephalomyelitis (PEM) and paraneoplastic sensory neuronopathy (PSN) are clinically welldefined, frequently overlapping, and almost always associated with anti-Hu antibodies (i.e. type 1 anti-neuronal nuclear autoantibodies) and small-cell lung cancer [1,2]. The etiology of PEM/PSN syndrome and other paraneoplastic syndromes is still unknown. The PEM/ PSN syndrome is characterized by a high titer of antiHu IgG antibodies in the serum and cerebrospinal fluid (CSF), the presence of inflammatory infiltrates of T cells and B cells in the nervous system, and the existence of a tumor, usually small-cell lung cancer [3–6]. * Corresponding author. Tel.: +81-97-586-5814; fax: + 81-97-5496502. E-mail address: [email protected] (T. Kumamoto).
These characteristics suggest that a mechanism mediated by the humoral or cell-mediated immunities may play a central role in the pathogenesis of this disease. PSN is sometimes manifested by cranial nerve involvement, seen as trigeminal, facial, or abducens nerve palsies [1]. However, only a few cases of PSN with multiple cranial nerve involvement have been reported.
2. Case report A 71-year-old man noticed progressive burning pain in his feet and numbness of all extremities 4 months prior to admission. On admission, the patient received a neurologic examination which validated sensory ataxia, Romberg’s sign, stocking-glove sensory impairment of all modalities, and areflexia. The CSF protein concentration was 75 mg/dl (normal is below 45 mg/dl) with
0303-8467/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 1 ) 0 0 1 9 0 - 1
S. Fujimoto et al. / Clinical Neurology and Neurosurgery 104 (2002) 98–102
normal CSF composition. Sensory nerve conduction velocities were markedly decreased. Sural nerve biopsy demonstrated marked loss of both large and small myelinated fibers with no inflammatory infiltrates or malignant cell invasion. Multiple radiographs of the skull, magnetic resonance imaging (MRI) of the brain, and scintigram studies of the bone showed no tumor metastasis or invasion into intracranial regions. A chest radiograph and computer tomography study showed a small mass in the middle lung field with enlarged mediastinal lymphnodes, diagnosed by trans-mediastinoscopic biopsy as small-cell lung cancer. No anti-Yo antibody was detected in the serum, but high titers of anti-Hu antibodies were present in the serum (a titer of 16 000) and CSF (a titer of 800). Two months following admission, the patient developed anisocoria, left abducens and facial nerve palsies, sensory impairment on the left side of the face, hearing loss in the left ear, dysarthria, dysphagia, and tongue atrophy. The size of the pupil in the left eye was larger than that in the right. The left pupil lost light reflex, but contracted with 0.025% pilocalpin, showing tonicity. The patient exhibited multiple cranial nerve palsies involving the left trigeminal, abducens, facial, and acoustic nerves and the glossopharyngeal, vagus, and hypoglossal nerves. MRI of the brain still revealed no abnormal findings in the intracranial regions. The patient received systemic chemotherapy, but died of res-
99
piratory failure due to pneumonia after 13 months of illness. On postmortem examination, the brain appeared to be normal and weighed 1230 g before fixation. The brainstem and cranial nerves also appeared to be normal. Neither metastasis nor direct invasion of malignant cells was present within the base of the skull, the leptomeninges, or the brainstem. Histopathologic examination revealed marked degeneration of the dorsal root ganglia and the posterior columns of the spinal cord with gliosis and a loss of myelin. The dorsal roots of the spinal cord at the cervical, thoracic, and lumber levels showed marked loss of myelinated fibers and endoneurial fibrosis, while the ventral roots were apparently normal. Marked neuronal loss with gliosis was observed in both the cuneatus and gracilis nuclei. Marked degeneration was seen in the medial lemniscus of the medulla, pons, and midbrain, accompanied by perivascular lymphocytic infiltration and gliosis. There was also a marked decrease in the number of neurons in the ventrolateral nuclei of the thalamus. The spinothalamic tract, however, was normal. In the brainstem, neuronal loss and gliosis was present in the nuclei of the left trigeminal, abducens, facial, acoustic, glossopharyngeal, and vagus nerves and in the nuclei of the hypoglossal nerves bilaterally. These findings were especially pronounced in the nuclei of the facial and trigeminal nerves, which were nearly devoid of normal
Fig. 1. (A, B) Facial nerve nuclei. (C, D) Spinal tract of the trigeminal nerves. The right facial nerve nuclei and the spinal tract of the right trigeminal nerve were normal (A, C). The left facial nerve nuclei were nearly devoid of normal neurons (B). There were losses of axons and myelin sheath in the spinal tract of the left trigeminal nerve (D). Bar =50 mm.
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S. Fujimoto et al. / Clinical Neurology and Neurosurgery 104 (2002) 98–102
3. Discussion
Fig. 2. Immunostaining for ICAM-1 and LFA-1 in the brains of the patient and a neurologically normal individual. In the normal cerebrum, staining for ICAM-1 was weakly positive on the endothelia of some microvessels (A). Staining for LFA-1 was positive on some interstitial cells, but the intensity was weak (B). In the patient, staining for ICAM-1 was strongly positive on the endothelia of some microvessels (C). Staining for LFA-1 was positive on infiltrated mononuclear cells around the microvessels (D). The expressions of ICAM-1 (E) and LFA-1 (F) in the medulla were greater than those in the cerebrum. Bar = 50 mm.
neurons (Fig. 1). There were losses of axons and myelin sheath in the spinal tract of the left trigeminal nerve (Fig. 1D). The hypoglossal nerve nuclei bilaterally revealed few perivascular lymphocytic infiltrates, very mild gliosis, and little neuronal loss. Immunohistochemistry was performed on the frozen sections of cerebrum and brainstem obtained from this patient and from neurologically normal individuals (controls). Intracellular adhesion molecule-1 (ICAM-1, dilution 1: 40; Dako, Glostrup, Denmark) was taken up by the endothelia of the microvessels of the patient’s brain, particularly in the brainstem (Fig. 2A, C and E). Similarly, lymphocyte function-associated molecule-1 (LFA-1, dilution 1: 40; Dako), the ligand for ICAM-1, expressed on the infiltrated mononuclear cells around the microvessels of the patient’s brain, particularly around the brainstem (Fig. 2B, D and F). Most of these perivascular infiltrated mononuclear cells were positive for CD8 and some were positive for CD4. The EBM11 + mononuclear cells (probably reactive microglial cells) found in the perivascular and interstitial areas were concentrated in the patient’s brainstem (data not shown).
In the study of this patient, the most interesting clinical feature was the multiple cranial nerve palsies associated with PSN. Cranial nerve involvement ultimately included the trigeminal, abducens, facial, acoustic, glossopharyngeal, vagus, and hypoglossal nerves, just as in Garcin syndrome [7]. This syndrome is characterized by total unilateral cranial nerve palsies (at least more than seven ipsilateral cranial nerve palsies), without either sensory or motor long tract disturbances, and without intracranial hypertension. In general, neurologic involvement associated with cancer results from (1) the direct invasion or metastasis of a tumor into the base of the skull, the meninges, or the brain parenchyma; (2) irradiation of the brain or cranium, or antineoplastic chemotherapy; or (3) an indirect or ‘remote’ effect of a primary systemic malignancy of the nerve tissues or other organs [8]. Our patient had received neither chemotherapy nor irradiation. Pathologic examination showed no metastasis or direct invasion of malignant cells intracranially, specifically within the base of the skull, the leptomeninges, and the brainstem. The principal findings within the central nervous system were selective neuronal loss in the cranial nerve nuclei of the left trigeminal, abducens, facial, acoustic, glossopharyngeal, and vagus nerves and of the hypoglossal nerves bilaterally, and gliosis and perivascular inflammation throughout the brainstem. These findings suggest a diagnosis of PEM, first described by Henson et al. [9]. Our patient initially had PSN and subsequently developed PEM. The multiple cranial nerve palsies, including a tonic left pupil, in our patient were likely due to a remote effect of small-cell lung cancer. Cranial nerve involvement is commonly reported with PEM/PSN [1,2,10–15]. Most patients with this syndrome, however, exhibit palsies of fewer than three cranial nerves. To our knowledge, only one reported case displayed multiple cranial nerve palsies involving the optic, occulomotor, trochlear, abducens, trigeminal, facial, vagus, and hypoglossal nerves [15]. The patient had bronchial carcinoma but the patient’s serum and CSF were not examined for the presence of autoantibody, such as anti-Hu antibody (Table 1). Histologic analysis of our patient’s brain showed inflammatory infiltrates of the mononuclear cells, mainly around the microvessels of the brainstem. These cells were mainly CD8+ T cells, with some CD4+ T cells and some EBM11+ cells (probably reactive microglial cells), as previously reported by Graus [3]. These results suggest that an immune-mediated mechanism, such as cell-mediated cytotoxicity, may play a central role in the pathogenesis of this disease. The expression of ICAM-1 and LFA-1 in the central nervous system has been studied in immune-mediated diseases, such as multiple sclerosis (MS), but seldom in
S. Fujimoto et al. / Clinical Neurology and Neurosurgery 104 (2002) 98–102
101
Table 1 PEM/PSN with cranial nerve involvement Author
Patient age/sex
Clinical diagnosis
Cranial nerve involvement
Tumor type
Anti-Hu antibody
Horwich et al. [1]
60/F 64/F 42/F 49/F 42/M 56/M 54/F 49/M 63/M 60/F 70/M 70/M 63/F 54/F 71/M
SSN SSN SSN SSN BE BE SSN SSN PEM PEM/PSN PEM/PSN PEM/PSN BE PEM PSN
VI V VII, VIII XII III, V II–VII, IX, X, XII VIII VIII II–IV VIII VII, IX, X VI, VII III, IV, VI VI, VII, IX, X V–X, XII
Anaplastic carcinoma Synovial sarcoma Parotid tumor Ovarian tumor Adenocarcinoma of lung Bronchial carcinoma SCLC SCLC SCLC SCLC Matastatic tumor Prostata carcinoma Unknown SCLC SCLC
NE NE NE NE NE NE + + NE + + + + NE +
Reddy et al. [9] Pillay et al. [14] Anderson et al. [10] Boghen et al. [11] Dalmau et al. [2]
Crino et al. [12] Dropcho [13] Present case
PEM, paraneoplastic encephalomyelitis; PSN, paraneoplastic sensory neuronopathy; M, male; F, female; SSN, subacute sensory neuropathy; BE, brainstem encephalitis; SCLC, small-cell lung cancer; NE, not examined.
paraneoplastic syndromes [16,17]. Both adhesion molecules may be involved in cell-mediated cytotoxicity and may be important in the initiation or perpetuation of the immune response [18– 21]. Sobel et al. have reported that the expression of ICAM-1 increased on microvessels in active MS plaques, while numerous LFA-1-positive mononuclear cells were found in the perivascular inflammatory cuff adjacent to active MS plaques [17]. In our present study, we observed enhanced expression of ICAM-1 on the endothelia of microvessels and enhanced expression of LFA-1 on the infiltrated mononuclear cells around the microvessels, in the patient’s brain, particularly in the brainstem. These findings suggest increases in lymphocyte-endothelial cell adhesion and microglia-mediated immune response, which in turn suggest that an immune-mediated mechanism may play a role in the pathogenesis of multiple cranial nerve palsies in this disease.
Acknowledgements We are most grateful to Mrs. M. Ono for her technical assistance. This is supported by the Neuroimmunological Disease Research Committee, Ministry of Health and Welfare of Japan.
References [1] Horwich MS, Cho L, Porro RS, Posner JB. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol 1977;2:7 – 19. [2] Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy: a clinical study of 71 patients. Medicine 1992;71:59 –72.
[3] Graus F, Ribalta T, Campo E, Monforte R, Urbano A, Rozman C. Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis. Neurology 1990;40:219 – 22. [4] Dalmau J, Furneaux HM, Gralla RJ, Kris MG, Posner JB. Detection of the anti-Hu antibody in the serum of patients with small-cell lung cancer: a quantitative Western blot analysis. Ann Neurol 1990;27:544 – 52. [5] Dalmau J, Furneaux HM, Rosenblum MK, Graus F, Posner JB. Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology 1991; 41:1757 – 64. [6] Jean WC, Dalmau J, Ho A, Posner JB. Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis. Neurology 1994;44:140 – 7. [7] Guillain G, Alajouanine TH, Garcin R. Le syndrome paralytique unilate´ ral global des nerfs craniens. Bull Me´ m Soc Me´ d Hoˆ p Paris 1926;50:456 – 60. [8] McLeod JG. Paraneoplastic neuropathies. In: Dyck PJ, et al., editors. Peripheral Neuropathy. Philadelphia: WB Saunders, 1993:1583. [9] Henson RA, Urich H. Encephalomyelitis with carcinoma. In: Henson RA, Urich H, editors. Cancer and The Nervous System: The Neurological Manifestations of Systemic Malignant Disease. Oxford: Blackwell Scientific Publications, 1982:314 – 45. [10] Reddy RV, Vakili ST. Midbrain encephalitis as a remote effect of a malignant neoplasm. Arch Neurol 1981;38:781 – 2. [11] Anderson NE, Rosenblum MK, Graus F, Wiley RG, Posner JB. Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer. Neurology 1988;38:1391 – 8. [12] Boghen D, Sebag M, Michaud J. Paraneoplastic optic neuritis and encephalomyelitis report of a case. Arch Neurol 1988;45:353 – 6. [13] Crino PB, Galetta SL, Sater RA, Raps EC, Witte A, Roby D, Rosenquist AC. Clinicopathologic study of paraneoplastic brainstem encephalitis and ophthalmoparesis. J Neuro-Opthalmol 1996;16:44 – 8. [14] Dropcho EJ. Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis. Ann Neurol 1996;39:659 – 67.
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[15] Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and ‘optic neuritis’: paraneoplastic effects of bronchial carcinoma. Neurology 1984;34:788 – 91. [16] Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 1995;37:424 – 35. [17] Sobel RA, Mitchell ME, Fondren G. Intercellular adhesion molecule-1 (ICAM-1) in cellular reactions in the human central nervous system. Am J Pathol 1990;136:1309 –16. [18] Dougherty GJ, Murdoch S, Hogg N. The function of human intercellular adhesion molecule-1 (ICAM-1) in the generation of an immune response. Eur J Immunol 1988;18:35 –9.
[19] Makgoba MW, Sanders ME, Ginther Luce GE, Gugel EA, Dustin ML, Springer TA, Shaw S. Functional evidence that intercellular adhesion molecule-1 (ICAM-1) is a ligand for LFA1-dependent adhesion in T cell-mediated cytotoxicity. Eur J Immunol 1988;18:637 – 40. [20] Maio M, Tessitori G, Pinto A, Temponi M, Colombatti A, Ferrone S. Differential role of distinct determinants of intercellular adhesion molecule-1 in immunologic phenomena. J Immunol 1989;143:181 – 8. [21] Bierer BE, Burakoff SJ. T cell adhesion molecules. FASEB J 1988;2:2584 – 90.
A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies Shin Fujimoto a, Toshihide Kumamoto a,*, Tomoko Ito a, Kunihiro Sannomiya a, Takashi Inuzuka b, Tomiyasu Tsuda a a
Third Department of Internal Medicine, Oita Medical Uni6ersity, Hasama 1 -1, Oita 879 -5593, Japan b Department of Gerontology, Gifu Uni6ersity School of Medicine, Gifu, Japan
Received 2 February 2001; received in revised form 6 September 2001; accepted 23 November 2001
Abstract Only a few cases of paraneoplastic neurologic syndrome with multiple cranial palsies have been reported. This is the case report of a patient with small-cell lung cancer and a high titer of anti-Hu antibodies who developed a tonic left pupil and multiple cranial nerve palsies, including palsies of the left fifth through tenth nerves and both twelfth nerves, as in Garcin syndrome showing at least more than seven ipsilateral cranial nerve palsies, in the course of paraneoplastic sensory neuronopathy (PSN). Pathologic examination revealed no metastasis or direct invasion of malignancy with gliosis and perivascular inflammation throughout the brainstem, indicating paraneoplastic encephalomyelitis (PEM). The numbers of EBM11 + cells (probably reactive microglia), CD8+ cells, and CD4 + cells increased. Intracellular adhesion molecule-1 and lymphocyte function associated molecule-1 were expressed intensely on the endothelia of microvessels and were found to have infiltrated mononuclear cells around microvessels in the brainstem. Multiple cranial nerve palsies and their effects including the tonic pupil are likely due to the paraneoplastic effect of the primary systemic malignancy. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Paraneoplastic syndrome; Paraneoplastic encephalomyelitis; Paraneoplastic sensory neuronopathy; Multiple cranial nerve palsies; Tonic pupil; Adhesion molecules
1. Introduction Paraneoplastic encephalomyelitis (PEM) and paraneoplastic sensory neuronopathy (PSN) are clinically welldefined, frequently overlapping, and almost always associated with anti-Hu antibodies (i.e. type 1 anti-neuronal nuclear autoantibodies) and small-cell lung cancer [1,2]. The etiology of PEM/PSN syndrome and other paraneoplastic syndromes is still unknown. The PEM/ PSN syndrome is characterized by a high titer of antiHu IgG antibodies in the serum and cerebrospinal fluid (CSF), the presence of inflammatory infiltrates of T cells and B cells in the nervous system, and the existence of a tumor, usually small-cell lung cancer [3–6]. * Corresponding author. Tel.: +81-97-586-5814; fax: + 81-97-5496502. E-mail address: [email protected] (T. Kumamoto).
These characteristics suggest that a mechanism mediated by the humoral or cell-mediated immunities may play a central role in the pathogenesis of this disease. PSN is sometimes manifested by cranial nerve involvement, seen as trigeminal, facial, or abducens nerve palsies [1]. However, only a few cases of PSN with multiple cranial nerve involvement have been reported.
2. Case report A 71-year-old man noticed progressive burning pain in his feet and numbness of all extremities 4 months prior to admission. On admission, the patient received a neurologic examination which validated sensory ataxia, Romberg’s sign, stocking-glove sensory impairment of all modalities, and areflexia. The CSF protein concentration was 75 mg/dl (normal is below 45 mg/dl) with
0303-8467/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 1 ) 0 0 1 9 0 - 1
S. Fujimoto et al. / Clinical Neurology and Neurosurgery 104 (2002) 98–102
normal CSF composition. Sensory nerve conduction velocities were markedly decreased. Sural nerve biopsy demonstrated marked loss of both large and small myelinated fibers with no inflammatory infiltrates or malignant cell invasion. Multiple radiographs of the skull, magnetic resonance imaging (MRI) of the brain, and scintigram studies of the bone showed no tumor metastasis or invasion into intracranial regions. A chest radiograph and computer tomography study showed a small mass in the middle lung field with enlarged mediastinal lymphnodes, diagnosed by trans-mediastinoscopic biopsy as small-cell lung cancer. No anti-Yo antibody was detected in the serum, but high titers of anti-Hu antibodies were present in the serum (a titer of 16 000) and CSF (a titer of 800). Two months following admission, the patient developed anisocoria, left abducens and facial nerve palsies, sensory impairment on the left side of the face, hearing loss in the left ear, dysarthria, dysphagia, and tongue atrophy. The size of the pupil in the left eye was larger than that in the right. The left pupil lost light reflex, but contracted with 0.025% pilocalpin, showing tonicity. The patient exhibited multiple cranial nerve palsies involving the left trigeminal, abducens, facial, and acoustic nerves and the glossopharyngeal, vagus, and hypoglossal nerves. MRI of the brain still revealed no abnormal findings in the intracranial regions. The patient received systemic chemotherapy, but died of res-
99
piratory failure due to pneumonia after 13 months of illness. On postmortem examination, the brain appeared to be normal and weighed 1230 g before fixation. The brainstem and cranial nerves also appeared to be normal. Neither metastasis nor direct invasion of malignant cells was present within the base of the skull, the leptomeninges, or the brainstem. Histopathologic examination revealed marked degeneration of the dorsal root ganglia and the posterior columns of the spinal cord with gliosis and a loss of myelin. The dorsal roots of the spinal cord at the cervical, thoracic, and lumber levels showed marked loss of myelinated fibers and endoneurial fibrosis, while the ventral roots were apparently normal. Marked neuronal loss with gliosis was observed in both the cuneatus and gracilis nuclei. Marked degeneration was seen in the medial lemniscus of the medulla, pons, and midbrain, accompanied by perivascular lymphocytic infiltration and gliosis. There was also a marked decrease in the number of neurons in the ventrolateral nuclei of the thalamus. The spinothalamic tract, however, was normal. In the brainstem, neuronal loss and gliosis was present in the nuclei of the left trigeminal, abducens, facial, acoustic, glossopharyngeal, and vagus nerves and in the nuclei of the hypoglossal nerves bilaterally. These findings were especially pronounced in the nuclei of the facial and trigeminal nerves, which were nearly devoid of normal
Fig. 1. (A, B) Facial nerve nuclei. (C, D) Spinal tract of the trigeminal nerves. The right facial nerve nuclei and the spinal tract of the right trigeminal nerve were normal (A, C). The left facial nerve nuclei were nearly devoid of normal neurons (B). There were losses of axons and myelin sheath in the spinal tract of the left trigeminal nerve (D). Bar =50 mm.
100
S. Fujimoto et al. / Clinical Neurology and Neurosurgery 104 (2002) 98–102
3. Discussion
Fig. 2. Immunostaining for ICAM-1 and LFA-1 in the brains of the patient and a neurologically normal individual. In the normal cerebrum, staining for ICAM-1 was weakly positive on the endothelia of some microvessels (A). Staining for LFA-1 was positive on some interstitial cells, but the intensity was weak (B). In the patient, staining for ICAM-1 was strongly positive on the endothelia of some microvessels (C). Staining for LFA-1 was positive on infiltrated mononuclear cells around the microvessels (D). The expressions of ICAM-1 (E) and LFA-1 (F) in the medulla were greater than those in the cerebrum. Bar = 50 mm.
neurons (Fig. 1). There were losses of axons and myelin sheath in the spinal tract of the left trigeminal nerve (Fig. 1D). The hypoglossal nerve nuclei bilaterally revealed few perivascular lymphocytic infiltrates, very mild gliosis, and little neuronal loss. Immunohistochemistry was performed on the frozen sections of cerebrum and brainstem obtained from this patient and from neurologically normal individuals (controls). Intracellular adhesion molecule-1 (ICAM-1, dilution 1: 40; Dako, Glostrup, Denmark) was taken up by the endothelia of the microvessels of the patient’s brain, particularly in the brainstem (Fig. 2A, C and E). Similarly, lymphocyte function-associated molecule-1 (LFA-1, dilution 1: 40; Dako), the ligand for ICAM-1, expressed on the infiltrated mononuclear cells around the microvessels of the patient’s brain, particularly around the brainstem (Fig. 2B, D and F). Most of these perivascular infiltrated mononuclear cells were positive for CD8 and some were positive for CD4. The EBM11 + mononuclear cells (probably reactive microglial cells) found in the perivascular and interstitial areas were concentrated in the patient’s brainstem (data not shown).
In the study of this patient, the most interesting clinical feature was the multiple cranial nerve palsies associated with PSN. Cranial nerve involvement ultimately included the trigeminal, abducens, facial, acoustic, glossopharyngeal, vagus, and hypoglossal nerves, just as in Garcin syndrome [7]. This syndrome is characterized by total unilateral cranial nerve palsies (at least more than seven ipsilateral cranial nerve palsies), without either sensory or motor long tract disturbances, and without intracranial hypertension. In general, neurologic involvement associated with cancer results from (1) the direct invasion or metastasis of a tumor into the base of the skull, the meninges, or the brain parenchyma; (2) irradiation of the brain or cranium, or antineoplastic chemotherapy; or (3) an indirect or ‘remote’ effect of a primary systemic malignancy of the nerve tissues or other organs [8]. Our patient had received neither chemotherapy nor irradiation. Pathologic examination showed no metastasis or direct invasion of malignant cells intracranially, specifically within the base of the skull, the leptomeninges, and the brainstem. The principal findings within the central nervous system were selective neuronal loss in the cranial nerve nuclei of the left trigeminal, abducens, facial, acoustic, glossopharyngeal, and vagus nerves and of the hypoglossal nerves bilaterally, and gliosis and perivascular inflammation throughout the brainstem. These findings suggest a diagnosis of PEM, first described by Henson et al. [9]. Our patient initially had PSN and subsequently developed PEM. The multiple cranial nerve palsies, including a tonic left pupil, in our patient were likely due to a remote effect of small-cell lung cancer. Cranial nerve involvement is commonly reported with PEM/PSN [1,2,10–15]. Most patients with this syndrome, however, exhibit palsies of fewer than three cranial nerves. To our knowledge, only one reported case displayed multiple cranial nerve palsies involving the optic, occulomotor, trochlear, abducens, trigeminal, facial, vagus, and hypoglossal nerves [15]. The patient had bronchial carcinoma but the patient’s serum and CSF were not examined for the presence of autoantibody, such as anti-Hu antibody (Table 1). Histologic analysis of our patient’s brain showed inflammatory infiltrates of the mononuclear cells, mainly around the microvessels of the brainstem. These cells were mainly CD8+ T cells, with some CD4+ T cells and some EBM11+ cells (probably reactive microglial cells), as previously reported by Graus [3]. These results suggest that an immune-mediated mechanism, such as cell-mediated cytotoxicity, may play a central role in the pathogenesis of this disease. The expression of ICAM-1 and LFA-1 in the central nervous system has been studied in immune-mediated diseases, such as multiple sclerosis (MS), but seldom in
S. Fujimoto et al. / Clinical Neurology and Neurosurgery 104 (2002) 98–102
101
Table 1 PEM/PSN with cranial nerve involvement Author
Patient age/sex
Clinical diagnosis
Cranial nerve involvement
Tumor type
Anti-Hu antibody
Horwich et al. [1]
60/F 64/F 42/F 49/F 42/M 56/M 54/F 49/M 63/M 60/F 70/M 70/M 63/F 54/F 71/M
SSN SSN SSN SSN BE BE SSN SSN PEM PEM/PSN PEM/PSN PEM/PSN BE PEM PSN
VI V VII, VIII XII III, V II–VII, IX, X, XII VIII VIII II–IV VIII VII, IX, X VI, VII III, IV, VI VI, VII, IX, X V–X, XII
Anaplastic carcinoma Synovial sarcoma Parotid tumor Ovarian tumor Adenocarcinoma of lung Bronchial carcinoma SCLC SCLC SCLC SCLC Matastatic tumor Prostata carcinoma Unknown SCLC SCLC
NE NE NE NE NE NE + + NE + + + + NE +
Reddy et al. [9] Pillay et al. [14] Anderson et al. [10] Boghen et al. [11] Dalmau et al. [2]
Crino et al. [12] Dropcho [13] Present case
PEM, paraneoplastic encephalomyelitis; PSN, paraneoplastic sensory neuronopathy; M, male; F, female; SSN, subacute sensory neuropathy; BE, brainstem encephalitis; SCLC, small-cell lung cancer; NE, not examined.
paraneoplastic syndromes [16,17]. Both adhesion molecules may be involved in cell-mediated cytotoxicity and may be important in the initiation or perpetuation of the immune response [18– 21]. Sobel et al. have reported that the expression of ICAM-1 increased on microvessels in active MS plaques, while numerous LFA-1-positive mononuclear cells were found in the perivascular inflammatory cuff adjacent to active MS plaques [17]. In our present study, we observed enhanced expression of ICAM-1 on the endothelia of microvessels and enhanced expression of LFA-1 on the infiltrated mononuclear cells around the microvessels, in the patient’s brain, particularly in the brainstem. These findings suggest increases in lymphocyte-endothelial cell adhesion and microglia-mediated immune response, which in turn suggest that an immune-mediated mechanism may play a role in the pathogenesis of multiple cranial nerve palsies in this disease.
Acknowledgements We are most grateful to Mrs. M. Ono for her technical assistance. This is supported by the Neuroimmunological Disease Research Committee, Ministry of Health and Welfare of Japan.
References [1] Horwich MS, Cho L, Porro RS, Posner JB. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol 1977;2:7 – 19. [2] Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy: a clinical study of 71 patients. Medicine 1992;71:59 –72.
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