Neuroimmunology in Clinical Practice - part 8 ppt

188 BERNADETTE KALMAN imaging study. J Neurol Neurosurg Psychiatry, 68, 170–7. Sarwar, H., McGrath, H. Jr. and Espinoza, L.R. 2005. Successful treatment of long-standing neuro- Behçet’s disease with infliximab. J Rheumatol, 32, 181–3. Wadia, N. and Williams, E. 1957. Behçet’s syndrome with neurological complications. Brain, 80, 59– 71. Wechsler, B., Huong, L.T., de Gennes, L.C., et al. 1989. Arterial involvement in Behçet’s disease. Rev Med Interne, 10, 303–11. Wolf, S.M., Schotland, D.L. and Phillips, L.L., 1965. Involvement of nervous system in Behçet’s syn- drome. Arch Neurol, 12, 315–25. Yurdakul, S., Gunaydin, I., Tuzun, Y. et al. 1988. The prevalence of Behçet’s syndrome in a rural area in northern Turkey. J Rheumatol, 15, 820–2. NICP_C12 03/05/2007 10:39 AM Page 188 Hashimoto’s thyroiditis is caused by a chronic lym- phocytic inflammation in 3–4% of the population. It typically occurs in middle-aged women. Affected individuals may be hypo-, hyper- or euthyroid. Multiple antithyroid antibodies, most commonly including those to thyroid peroxidase and thyroglo- bulin, are present. Ultrasonogram shows hypoechoic thyroid tissue, and fine-needle biopsy reveals infiltra- tion by T lymphocytes, plasma cells, and colloid accumulation and cell detritus in the thyroid gland (Seipelt et al., 2005). The first patient with Hashimoto’s thyroiditis and altered consciousness, myoclonus, and stroke- like episodes was reported by Brain et al. (1966). “Hashimoto’s encephalopathy” was soon coined for the central nervous system (CNS) disorder asso- ciated with autoimmune thyroiditis and varying thyroid function. The existence of Hashimoto’s encephalopathy as an entity, however, has been debated because of the lack of evidence indicative of a causative relationship between thyroid auto- immunity and encephalitis (Sunil and Mariash, 2001). Mahmud et al. (2003) recently proposed using the term “Steroid responsive encephalopathy associated with Hashimoto’s thyroiditis” (SREHT), which is being adopted here. SREHT is a rare, potentially life-threatening but treatable condition characterized by intermittent con- fusions, impaired consciousness, psychosis, hallu- cinations, seizures, stroke-like episodes, myoclonus, and tremor (Shaw et al., 1991). The seizures may be myoclonic, tonic-clonic generalized, or nonconvul- sive status epilepticus that is difficult to control. Less common presentations of SREHT include isolated global amnesia or amnesia with other features of encephalopathy ( Jacobs et al., 2006). The clinical presentation has been attributed to an underlying vasculitic process. The pathogenic significance of antithyroid antibodies remains uncertain. These antibodies are detected in 3–4% of the general population, and their presence may only indicate a predisposition to developing multiple autoantibodies (McKnight et al., 2005). The electroencephalogram (EEG) typically shows slowing and elevated proteins may be present in the cerebrospinal fluid (CSF). Magnetic resonance imaging (MRI) may show multifocal abnormalities in the cerebral white matter or brain atrophy, but imaging is unrevealing in about half of the patients. Autopsy reports usually reveal perivenular and arteriolar infiltration by pre- dominantly T lymphocytes throughout the brain including the hemispheral gray and white matter, basal ganglia, brainstem, and the leptomeninges. Diffuse gliosis is present in the cortical and deep gray matter, hippocampi, and the parenchymal white matter (Duffey et al., 2003; Nolte et al., 2000; Shibata et al., 1992). The extent of inflammatory changes in postmortem studies is often influenced by the preceding high-dose corticosteroid therapy. The recent observation that euthyroid patients with auto- immune thyroiditis have impaired brain perfusion on single photon emission computed tomography further supports the relationship between a cerebral involvement and Hashimoto’s thyroiditis (Zettinig et al., 2003). The short list of differential diagnosis for SREHT includes Creutzfeld–Jakob disease, Sjögren’s syn- drome, CNS complications of other connective tissue disorders and vasculitides, which usually can be sorted out based on EEG, serological and CSF studies, and thyroid work up. A nonvasculitic autoimmune inflammatory meningoencephalitis has also been described in patients with Hashimoto’s thyroiditis, Sjögren’s syndrome, and systemic lupus erythemato- sus ( Joseph et al., 2004). Despite the obscure etiology, SREHT is a treatable condition. Thyroid replacement therapy alone may improve some aspects of the cognitive abnormalities, while the neurological condition best responds to corticosteroids or plasma exchange. 13 Steroid-responsive encephalopathy associated with Hashimoto’s thyroiditis Bernadette Kalman NICP_C13 03/05/2007 10:40 AM Page 189 190 BERNADETTE KALMAN Summary Hashimoto’s thyroiditis may be associated with a life-threatening but treatable encephalopathy characterized by altered consciousness, memory disturbances, seizures, myoclonus, psychosis, and stroke-like episodes. The causative relationship between thyroid autoimmunity and encephalitis remains uncertain, but the CNS pathology displays signs of a T-cell mediated vasculitic process affecting both the gray and white matter. A thorough diag- nostic work up is necessary to distinguish SREHT from other encephalopathies of immune and non- immune etiology, and to implement effective treat- ments as early as possible. References Brain, L., Jellinek, E.H. and Ball, K. 1966. Hashimoto’s disease and encephalopathy. Lancet, 2, 512–14. Duffey, P., Yee, S., Reid, I.N. and Bridges, L.R. 2003. Hashimoto’s encephalopathy: Postmortem findings after fatal status epilepticus. Neurology, 61, 1124–6. Jacobs, A., Root, J. and van Gorp, W. 2006, Isolated global amnesia associated with autoimmune thy- roiditis. Neurology, 66, 605. Josephs, K.A., Rubino, F.A. and Dickson, D.W. 2004. Nonvasculitic autoimmune inflammatory meningo- encephalitis. Neuropathology, 24, 149–52. Mahmud, F.H., Lteif, A.N., Renaud, D.L., Reed, A.M. and Brands, C.K. 2003. Steroid-responsive encephalo- pathy associated with Hashimoto’s thyroiditis in an adolescent with chronic hallucinations and depression: Case report and review. Pediatrics, 112, 686–90. McKnight, K., Jiang, Y., Hart, Y. et al. 2005. Serum antibodies in epilepsy and seizure-associated dis- orders. Neurology, 65, 1730–6. Nolte, K.W., Unbehaun, A., Sieker, H., Kloss, T.M. and Paulus, W. 2000. Hashimoto encephalopathy: A brainstem vasculitis? Neurology, 54, 769–70. Seipelt, M., Zerr, I., Nau, R. et al. 1999. Hashimoto’s encephalitis as a differential diagnosis of Creutzfeldt- Jakob disease. J Neurol Neurosurg Psychiatry, 66, 172–6. Sunil, G.S. and Mariash, C.N. 2001. Hashimoto’s encephalitis. J Clin Endocrinol Metab, 86, 947. Shaw, P.J., Walls, T.J., Newman, P.K., Cleland, P.G. and Cartlidge, N.E. 1991. Hashimoto’s encephalopathy: A steroid-responsive disorder associated with high anti-thyroid antibody titers – Report of 5 cases. Neurology, 41, 228–33. Shibata, N., Yamamoto, Y., Sunami, N., Suga, M. and Yamashita, Y. 1992. Isolated angiitis of the CNS associated with Hashimoto’s disease. Rinsho Shinkeigaku, 32, 191–8. Zettinig, G., Asenbaum, S., Fueger, B.J. et al. 2003. Increased prevalence of subclinical brain perfusion abnormalitis in patients with autoimmune thyroi- ditis: Evidence of Hashimoto’s encephalitis? Clin Endocrinol, 59, 637–43. NICP_C13 03/05/2007 10:40 AM Page 190 Rasmussen et al. (1958) reported three patients with focal seizures associated with chronic encepha- litis. Subsequently, the occurrence of chronic focal encephalitis with seizures was named Rasmussen’s encephalitis (RE) or Rasmussen’s syndrome (Piatt et al., 1988). A European consensus statement recently summarized the accumulated knowledge concern- ing the pathogenesis, diagnosis, and treatment of RE (Bien et al., 2005). RE is a sporadic disorder with unknown etiology. Because of the lymphocytic infiltration and microglial activation in the brain lesions, a viral cause was proposed (Rasmussen et al., 1958). However, sub- sequent studies failed to unequivocally support a viral etiology. The cause of immune activation remains to be determined. Clinical characteristics RE usually presents in childhood with six years the average age of onset, but approximately 10% of patients have adult onset (Oguni et al., 1991). Typically, partial motor seizures arise to affect vari- ous parts in the same side of the body and gradually expand over time. A focal motor deficit follows the onset of seizures and gradually progresses to hemi- paresis. The electroencephalogram (EEG) correlate of these abnormalities is a unilateral deterioration of the background activity with focal repetitive rhythmic discharges migrating from one area of the cortex to another one, but only in the same side. The question has been raised if the seizures directly contribute to neuronal loss and dysfunction or indirectly con- tribute to further pathological damage and neuro- logical deterioration by opening the blood–brain barrier to immune mediators (Bien et al., 2005). The time course and natural history of RE greatly vary among patients. In the initial “prodromal stage,” patients typically have low seizure frequency and occasionally mild hemiparesis with a median duration of 7.1 months (0 month to 8.1 years). In the “acute stage,” the seizures usually present as simple partial motor seizures or epilepsia partialis continua (EPC) with rising frequency, and a progressive neuro- logical deterioration develops with severe hemi- paresis, hemianopia, cognitive decline, and aphasia, if the dominant hemisphere is involved. In one-third of patients, this is the initial presentation of RE. The median duration of this stage is 8 months (4– 8 months). In the third or “residual stage,” patients still have frequent seizures but also suffer from per- manent neurological deficits (Bien et al., 2005). The seizures in RE are characterized by polymor- phism, frequent occurrence of EPC, and resistance to therapy. In the series of Oguni et al. (1991), simple partial motor seizures with unilateral motor deficits was the most common presentation noted in 77% of cases. Secondary generalized tonic-clonic seizures were detected in 42%, complex partial seizures with auto- matisms in 19%, and with subsequent unilateral motor spread in 31% of patients, while postural seizures were noted in 24% and somatosensory seizures in 21% of their 48 patients. EPC was observed in 56–92% of patients (Granata et al., 2003; Oguni et al., 1991). RE is very rarely associated with bilateral cerebral involvement with secondary spread of focal seizures or interictal activity and atrophy in the contralateral hemisphere (Hart and Andermann, 2000). Immune abnormalities The original observation implicating antibodies to the subunit 3 of the ionotropic glutamate receptor (GluR3) in RE was made in rabbits, which developed RE-like pathology and seizures after immunization with a GluR3 fusion protein for raising antibodies. Rogers et al. (1994) detected anti-GluR3 antibodies in the sera of three out of four patients with RE, one of whom responded to plasma exchange. Plasmapheresis or selective IgG immunoabsorption then became the standard treatment, but with varying success (Andrews et al., 1996; Antozzi et al., 1998). While 14 Rasmussen’s encephalitis Bernadette Kalman NICP_C14 04/05/2007 12:25PM Page 191 192 BERNADETTE KALMAN evidence suggests that anti-GluR3 antibodies mediate cytotoxic activation of the glutamate receptor in vitro and in vivo (Levite and Hermelin, 1999; Twyman et al., 1995) with or without complement activation in neurons and glial cells (He et al., 1998; Whitney and McNamara, 2000), recent studies argue against the specificity of GluR3 antibodies in RE. GluR3 anti- bodies are not present in the sera and cerebrospinal fluid (CSF) of all patients with RE, while they are detected in the sera and CSF of patients with other types of epilepsy syndromes in a proportion similar to that found in RE (Mantegazza et al., 2002; Wiendl et al., 2001). Therefore, the pathogenic significance and diagnostic relevance of anti-GluR3 antibodies in RE have been rejected. However, observations sup- port an immunoglobulin and complement-mediated pathogenesis, and ongoing research is investigating the role of antibodies other than anti-GluR3 in RE (Lang et al., 2004; Yang et al., 2002). Most recently, antibodies to human α7 nicotinic acetylcholine receptors (α7nAChR) were detected in two patients with acute phase disease out of nine patients with RE (Watson et al., 2005). These antibodies blocked acetylcholine-induced increase in intracellular free calcium and inhibited 125 I-α-bungarotoxin bind- ing in cells expressing α7nAChR. The authors postulate that these antibodies may act by blocking the α7nAChR that influence the release of a variety of excitatory neurotransmitters in the brain. In addition, these antibodies themselves may mediate immune attacks on neurons. A study of inflammatory infiltrates in brains of RE patients revealed T cells with restricted T-cell receptor (TCR) Vβ utilization and CDR3 (complement- arity determining region 3) conservation, suggest- ing the expansion of a few T-cell clones in RE lesions (Li et al., 1997). It was also proposed that cytotoxic T lymphocytes with granzyme B granules may attack neurons expressing major histocompatibility com- plex (MHC) class I antigens and induce neuronal apoptosis (Bien et al., 2002). Cleavage of the GluR3 molecule by granzyme B may generate immuno- genic epitopes for further cellular and humoral activation (Gahring et al., 2001). However, in the light of conflicting observations concerning the role of GluR3-specific antibodies in the pathogenesis of RE, this latter observation needs to be interpreted with caution, and the antigen specificity of cytotoxic T cells remains to be determined (Bien et al., 2005). Nevertheless, these studies suggest that RE is a prim- arily T-cell driven and immunoglobulin-mediated autoimmune condition. Pathology Robitaille (1991) classified the cortical pathology of RE into four stages that were recently adapted and further refined by Pardo et al. (2004) based on a comprehensive work up of 45 patients who under- went hemispherectomy for the treatment of RE. The four stages are characterized by the following changes: 1 Early stage: Focal inflammation, focal microglial and astroglial reaction, minimal or no neuronal injury, and perivascular or perineural T lympho- cytes in the superficial and deep neuronal layers of the cerebral cortex. 2 Intermediate stage: Increase in the magnitude of lymphocytic infiltration as well as in the microglial and astroglial reactions from focal to panlaminar distribution. Neuronal injury is evidenced by the presence of cytoplasmic and nuclear changes and by the increased amounts of perineuronal satellitosis. Neuronal degeneration, patchy neuronal dropout, and cytoarchitectural changes are also present. The lymphocytes are predominantly CD3+ T cells with predominantly CD8, but also CD4 expression. The presence of B cells and plasma cells is not characteristic. 3 Late stage: Significant decrease in the neuronal population in large focal or panlaminar distribu- tion along with gemistocytic astroglial reaction and microglial activation. Cortical atrophy and focal spongiosis are present. 4 End stage: Extensive destruction of the cerebral cortex with signs of cortical vacuolation or com- plete panlaminar neuronal dropout. Residual astrogliosis with minimal or no inflammatory changes are characteristic. These histological observations are consistent with a progressive immune-mediated process of neuronal damage associated with T lymphocytic and neuro- glial responses similar to that noted in other auto- immune central nervous system (CNS) diseases. This study also emphasizes the multifocal distribu- tion of pathology and the intraindividual hetero- geneity of stages in cortical lesions. The patchy nature of pathology implies that the site of biopsy, if needed, has to be carefully determined in early suspected RE, and that partial cortical resection cannot be therapeutic. The earlier the onset and the longer the duration of RE the heavier is the dis- ease burden, which underscores the importance NICP_C14 04/05/2007 12:25PM Page 192 Rasmussen’s encephalitis 193 of aggressive and early therapeutic interventions (Pardo et al., 2004). Electroencephalogram, EEG Polymorphic delta waves mixed with epileptiform activity can be detected early during the course over the affected hemisphere in most patients. In later stages, the background activity further deteriorates, and epileptiform discharges may occur not only over the ipsilateral but also over the contralateral hemi- sphere. Multifocal ictal discharges are usually seen only in the affected side. Subclinical ictal activity may also occur. Imaging Despite the inflammatory nature of pathology, gadolinium enhancement on T1-weighted MRI is very rare in RE (Bien et al., 2002; Granata et al., 2003). A progressive tissue loss is the predominant feature noted in longitudinal MRI monitoring (Fig. 14.1) (Bien et al., 2002, 2005; Chiapparini et al., 2003). Initially, a unilateral enlargement of CSF compart- ments, particularly in the peri-insular/peri-Sylvian region, with T2-weighted and FLAIR hyperintensity and occasional swelling in the cortical/subcortical regions may be noted. In addition to the hemispheral atrophy, the head of the caudate nucleus may also be diminished. The atrophic changes gradually pro- gress across the hemisphere. No calcification develops in the chronic atrophied lesions. In correlation with these images, Bien et al. (2002) also noted higher numbers of T lymphocytes and activated glial cells in the earlier as compared to later surgical specimens in 10 patients who were serially scanned and under- went surgical procedures. In another serial MRI study of seven children with pathology-proven RE between 12 months before and nine months after the onset of EPC, Kim et al. (2002) identified three patterns: 1 Normal initial MRI followed by hyperintensity and cortical atrophy over time. 2 Initial focal hyperintensity followed by decrease in extent and degree of signal intensity. 3 Sustained hyperintensity on all follow-up scans. Positron emission tomography (PET) and single photon emission computer tomography (SPECT) typically show decreased metabolism in the inter- ictal, and hypermetabolism in the ictal scans. These (a) (b) Fig. 14.1 Axial FLAIR images of a patient with RE. The onset of RE started with EPC initially affecting the right side of the face at age 7.5 years in this patient. MRI image (a) at age 8.5 years shows slight atrophy with hyperintense signal in the left hemisphere. The second image (b) four years later reveals marked left hemiatrophy. A few months later, the patient underwent hemispheral deafferentation. Histology showed typical features of RE. Since surgery, the patient has been free of seizures. The MRI studies were performed by Horst Urbach, M.D., Department of Radiology/Neuroradiology, University of Bonn, Germany, and generously provided by Christian G. Bien, M.D., Department of Epileptology, University of Bonn, Germany. NICP_C14 04/05/2007 12:25PM Page 193 194 BERNADETTE KALMAN images may guide brain biopsy, if needed, for sup- porting the diagnosis. Cerebrospinal fluid, CSF CSF studies are primarily needed to exclude the possibility of encephalitis of infectious etiology. Half of the patients with RE have normal CSF, while the remaining patients have mild lymphocytic pleocy- tosis, mildly elevated protein, and occasionally oligoclonal bands. Diagnostic criteria for RE Clinical, EEG, and MRI characteristics usually make the diagnosis of RE straightforward (Box 14.1) and leave only a short list of differential diagnoses. The alternative diagnoses may include viral, paraneo- plastic, or other autoimmune forms of encephalitides (e.g. anti-voltage-gated potassium channel (VGKC) antibody-mediated limbic encephalitis, Hashimoto encephalitis, vasculitides), unihemispheric epileptic syndromes (cortical dysplasia, tuberous sclerosis, stroke, Sturge–Weber syndrome), inherited metabolic disorders (mitochondrial encephalopathies, Alpers syndrome, Kufs disease), and acquired metabolic disorders associated with EPC (ketotic or nonketotic hyperglycaemia, type I diabetes and anti-GAD65 antibodies, renal and hepatic encephalopathies) (Bien et al., 2005). Treatment To prevent the progressive tissue loss and clinical deterioration, an early diagnosis with immune mod- ulatory (corticosteroids, plasma exchange, immuno- suppression) intervention or epilepsy surgery is necessary as soon as possible. Symptomatic treat- ments with antiepileptic drugs alone have consist- ently failed to control seizures in RE. Corticosteroids, plasmapheresis, IVIg, IgG immunoabsorption tech- niques, immunosuppression with tacrolimus, and the combination of these methods have resulted in variable outcomes, but only delayed the inevitable hemispherectomy (Bien et al., 2005). The effective- ness of immune ablative therapies is currently being investigated. Epilepsy surgery is eventually needed in all cases. Focal cortical resections are ineffective. Hemi- spherectomy or modern disconnective techniques are the only treatments that efficiently control seizures in RE. The latter techniques are superior because of the low procedure-related morbidity and no mortal- ity. The timing of surgery has to be individually evalu- ated taking into account potential consequences of surgery (hemiparesis, hemianopia, and language dysfunction in the case of the dominant hemisphere) and the damage caused by the ongoing pathology and seizure activity. Earlier surgery is advocated when the pathology is in the left hemisphere and the child approaches the teenage years (Freeman, A 1 Clinical: Focal seizures with or without EPC and unilateral cortical deficits 2 EEG: Unilateral slowing with or without epileptiform discharges and unilateral seizure onset 3 MRI: Unilateral focal cortical atrophy and at least one of the following: – Hyperintense T2/FLAIR signal in gray and white matter – Hyperintense T2/FLAIR signal or atrophy in the ipsilateral caudate head B 1 Clinical: EPC or progressive unilateral cortical deficits 2 MRI: Progressive unilateral focal cortical atrophy 3 MRI: Histopathology: T-cell dominated encephalitis, activated microglial cells and reactive astrogliosis; no significant presence of parenchymal macrophages, B cells or plasma cells and absence of viral inclusion bodies RE can be diagnosed if all three criteria of part A or two of three criteria in part B are present. Consideration of Part B is recommended only if the criteria in part A are not fulfilled. MRI needs to be performed with gadolinium to exclude enhancement, and a CT scan is necessary to exclude calcification. Gadolinium enhancement and calcification are features noted in unihemispheric vasculitis but not in RE. Box 14.1 Diagnostic criteria for RE (after Bien et al., 2005). NICP_C14 04/05/2007 12:25PM Page 194 Rasmussen’s encephalitis 195 2005). Complications of surgery potentially include intraoperative bleeding, hydrocephalus usually fol- lowing surgery by a few days to weeks, and super- ficial cortical hemosiderosis with hydrocephalus 10–20 years after the surgery. With the advent of computer tomography (CT) and MRI, early recog- nition and surgical treatment (shunting) of these complications became possible (Freeman 2005). Summary RE is considered to be a T-cell driven and immunoglobulin-mediated disorder of the brain with progressive unihemispheral tissue loss, accumu- lation of contralateral motor deficits, and seizures. The seizures are characterized by polymorphisms, EPC, and resistance to therapy. The multifocal distribution of pathology and the various stages of cortical lesions suggest that the site of biopsy, if needed, has to be carefully chosen in an early disease and that a partial resection cannot be thera- peutic. Immune modulatory treatments may delay but do not circumvent the ultimately always necessary hemispherectomy or disconnective sur- gical interventions. References Andrews, P.I., Dichter, M.A., Berkovic, S.F., Newton, M.R. and McNamara, J.O. 1996. Plasmapheresis in Rasmussen’s encephalitis. Neurology, 46, 242–6. Antozzi, C., Granata, T., Aurisano, N. et al. 1998. Long- term selective IgG immuno-adsorption improves Rasmussen’s encephalitis. Neurology, 51, 302–5. Bien, C.G., Granata, T., Antozzi, C., et al. 2005. Patho- genesis, diagnosis and treatment of Rasmussen encephalitis: A European consensus statement. Brain, 128, 454–1. Bien, C.G., Urbach, H., Decker, M. et al. 2002. Diagnosis and staging of Rasmussen’s encephalitis by serial MRI and histopathology. Neurology, 58, 250–7. Bien, C.G., Widman, G., Urbach, H. et al. 2002. The natural history of Rasmussen’s encephalitis. Brain, 125, 1751–9. Chiapparini, L., Granata, T., Farina, L. et al. 2003. Diagnostic imaging in 13 cases of Rasmussen’s encephalitis: Can early MRI suggest the diagnosis? Neuroradiology, 45, 171–83. Freeman, J.M. 2005. Rasmussen’s syndrome: Progress- ive autoimmune multi-focal encephalopathy. Review Article. Pediatr Neurol, 32, 295–9. Gahring, L.C., Carlson, N.G., Meyer, E.L. and Rogers, S.W. 2001. Cutting edge: Granzyme B proteolysis of a neuronal glutamate receptor generates an auto- antigen and is modulated by glycosylation. J Immunol, 166, 1433–8. Granata, T., Gobbi, G., Spreafico, R. et al. 2003. Rasmussen’s encephalitis: Early characteristics allow diagnosis. Neurology, 60, 422–5. Hart, Y. and Andermann, F. 2000. Rasmussen syndrome. In J.M. Oxbury, C.E. Polkey and M. Duchowny (eds.), Intractable Focal Epilepsy, WB Saunders, London, pp. 233–48. He, X.P., Patel, M., Whitney, K.D., Janumpalli, S., Tenner, A. and McNamara, J.O. 1998. Glutamate receptor GluR3 antibodies and death of cortical cells. Neuron, 20, 153–63. Kim, S.J., Park, Y.D., Pillai, J.J., Lee, M.R. and Smith, J.R. 2002. A longitudinal MRI study in children with Rasmussen syndrome. Pediatr Neurol, 27, 282–8. Lang, B., Watson, R., Bermudez, I., Sattelle, D., Jepson, J. and Vincent, A. 2004. Antibodies to neuronal alpha7 acetylcholine receptor in patients with Rasmussen’s encephalitis. (Abstract). J Neuroimmunol, 154, 192. Levite, M. and Hermelin, A. 1999. Autoimmunity to the glutamate receptor in mice-a model for Rasmussen’s encephalitis? J Autoimmun, 13, 73–82. Li, Y., Uccelli, A., Laxer, K.D. et al., 1997. Local-clonal expansion of infiltrating T lymphocytes in chronic encephalitis of Rasmussen. J Immunol, 158, 1428 – 37. Mantegazza, R., Bernasconi, P., Baggi, F. et al., 2002. Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol, 131, 179–85. Oguni, H., Andermann, F. and Rasmussen, T.B. 1991. The natural history of the syndrome of chronic encephalitis and epilepsy: A study of the MNI series of forty-eight cases. In F. Andermann (ed.), Chronic Encephalitis and Epilepsy. Rasmussen’s Syndrome, Butterworth-Heineman, Boston, pp. 7–35. Pardo, C.A., Vining, E.P.G., Guo, L., Skolasky, R.L., Carson, B.S. and Freeman, J.M. 2004. The pathology of Rasmussen syndrome: Stages of cortical involve- ment and neuropathological studies in 45 hemi- spherectomies. Epilepsia, 45, 516–26. Piatt, J.H. Jr., Hwang, P.A., Armstrong, D.C., Becker, L.E. and Hoffman, H.J. 1988. Chronic focal encephalitis (Rasmussen syndrome): Six cases. Epilepsia , 29, 268– 79. Rasmussen, T., Olszewski, J. and Lloyd-Smith, D. 1958. Focal seizures due to chronic localized encephalitis. Neurology, 8, 435–45. Robitaille, Y. 1991. Neuropathologic aspects of chronic encephalitis. In F. Andermann (ed.), Chronic Encephalitis and Epilepsy. Rasmussen’s Syndrome, Butterworth-Heineman, Boston, pp. 79–110. Rogers, S.W., Andrews, P.I. and Gahring, L.C. et al. 1994. Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science, 265, 648–51. Twyman, R.E., Gahring, L.C., Spiess, J. and Rogers, S.W. 1995. Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site. Neuron, 14, 755–62. NICP_C14 04/05/2007 12:25PM Page 195 196 BERNADETTE KALMAN Watson, R., Jepson, J.E.S., Bermudez, I., et al. 2005. α7- Acetylcholine receptor antibodies in two patients with Rasmussen encephalitis. Neurology, 65, 1802–4. Whitney, K.D. and McNamara, J.O. 2000. GluR3 autoantibodies destroy neural cells in a complement- dependent manner modulated by complement regu- latory proteins. J Neurosci, 20, 7307–16. Wiendl, H., Bien, C.G., Bernasconi, P. et al. 2001. GluR3 antibodies: Prevalence in focal epilepsy but no specificity for Rasmussen’s encephalitis. Neurology, 57, 1511–14. Yang, R., Puranam, R.S., Butler, L.S. et al. 2000. Autoimmunity to munc-18 in Rasmussen’s encepha- litis. Neuron, 28, 375–83. NICP_C14 04/05/2007 12:25PM Page 196 Susac et al. (1979) described the triad of encephalo- pathy, branch retinal artery occlusion, and deafness as a microangiopathy syndrome of the brain, retina, and cochlea; and Hoyt coined the term “Susac’s syndrome” (Neuroophthalmological Symposium, San Francisco, 1986). The prevalence of Susac’s syndrome is unknown, but numerous cases, pre- dominantly women aged 16–58, have been reported. The female to male ratio is 3:1. The disorder is often misdiagnosed as multiple sclerosis (MS) or acute dis- seminated encephalomyelitis (ADEM) (Susac, 1994; Susac et al., 2003). Clinical characteristics The course is usually relapsing-remitting or less frequently progressive, and becomes self-limited after 2–4 years with usually mild residual visual, hearing, or cognitive symptoms. A proportion of patients develop the sequelae of severe deafness and moderate dementia. Patients may not be aware of their hearing loss or visual impairment, particularly when the first symptom is encephalopathy. Some affected individuals present with incomplete triad (Susac, 1994). Encephalopathy Headaches frequently precede by a month or several months or coincide with the onset of a subacute encephalopathy. Migraine headaches are most fre- quently seen in those patients who present with branch retinal artery occlusion or hearing loss. The subacute encephalopathy usually presents with con- fusion, memory disturbances, bizarre or paranoid behavioral changes, and other psychiatric features. The encephalopathy occasionally progresses to stupor. The most characteristic neurological abnormalities include bilateral extensor plantar responses and pseudobulbar speech. Myoclonus and seizures also may develop. Some patients have focal neurological signs reflecting brainstem or cerebellar lesions, or transient paresthesias and hemiparesis not to be confused with transient ischemic attacks. Branch retinal artery occlusion The sequence of index events varies. The branch retinal artery occlusion may be a presenting symp- tom or follow the onset of the encephalopathy. The arterial occlusions are usually bilateral, and the infarcts involve varying segments of the retina with striking or unnoticed subjective visual impairment, depending on the central or peripheral location of infarcts (Fig. 15.1). Fluorescein angiography is a helpful tool for the diagnosis of branch retinal artery occlusions. In chronic stages, silver streaks replace the appearance of occluded arterioles in the fundus. Retinal artery wall (Gass) plaques may preferentially occur in the mid-segments of retinal arterioles. Hearing loss Bilateral hearing loss, tinnitus, vertigo, and nystagmus may also be the presentation of Susac’s syndrome. The underlying pathology includes microinfarcts in the apical part of the cochlea and in the semicircular canals resulting in hearing loss predominantly for the low to moderate frequency tones and prominent jerk nystagmus, respectively (Susac, 1994). Paraclinical studies Electroencephalogram (EEG) may reveal diffuse slowing during an acute episode of encephalopathy. T2-weighted and FLAIR (fluid-attenuated inversion recovery) MRI (magnetic resonance imaging) images demonstrate microinfarcts in the periventricular white matter, centrum semiovale, corpus callosum, as well as in the deep and cortical gray matter, cerebel- lum, and brainstem (Fig. 15.2). In acute and subacute phases, the lesions may enhance on T1-weighted 15 Susac’s syndrome Bernadette Kalman NICP_C15 03/05/2007 10:41 AM Page 197 [...]... protein, evidence of Serological associations (see Table 19.2) CRMP-5; AGNA-1; ANNA-1,3; VGKC; PCA-2; Ma2; neuropil AGNA-1; ANNA-1,2,3; PCA-2; amphiphysin; CRMP-5; ganglionic AChR; VGCC (P/Q or N); striational; GAD65; EFA6A Ma2; ANNA-1 CRMP-5 VGKC PCA-1,2,Tr; CRMP-5; AGNA-1; ANNA-1,2,3; VGCC (P/Q>N-type); GAD65; Zic4; GluR1 AGNA-1; ANNA-1,2,3; PCA-2; Ma2; CRMP-5; VGCC (P/Q>N-type) Amphiphysin CRMP-5;... blot and immunostaining patterns of reactivity ANNA-3, AGNA-1/ANNA-4, PCA-2, and PCA-Tr antibodies were described generically based on their distinctive patterns of immunofluorescence staining A specific protein antigen has not yet been defined in these instances, however, ANNA-3 and PCA-2 proteins are identifiable by neuronal and small-cell carcinoma western blots (Chan et al., 2001; Vernino and Lennon 2000)... ANNA-3 ANNA-4 PCA-1 PCA-2 PCA-Tr AGNA-1/ANNA-4 Amphiphysin Ab CRMP-5-IgG If pattern suggests GAD65 Ab If pattern suggests CRMP-5-IgG ELISA Striational Ab, Radioimmunoprecipitation VGCC (P/Q-Type) Ab VGCC (N-Type) Ab ACh Receptor (Muscle) Ab AChR (Ganglionic) Ab VGKC Ab If pattern indeterminate due to coexisting Abs If VGCC (P/Q-type or N-type), ganglionic AChR, VGKC or striational Abs detected CRMP-5 Western... protein tyrosine phosphatase-1 (DEP-1/CD1 48) , which is expressed by the sensory epithelia in the inner ear and by endothelial cells IgG purified from patients’ sera recognized the DEP-1/CS1 48 protein, bound to connexin 26 and human cochlea, and exerted antiproliferative effects on cells expressing DEP-1/CD1 48 These antibodies also had the capacity to induce a disease resembling CS in mice By computer-assisted... Amphiphysin CRMP-5; ANNA-1; 2, PCA-2 CRMP-5; recoverin CRMP-5; VGCC; amphiphysin; ganglionic AChR; VGKC; ANNA-1,2 ANNA-1; CRMP-5; ganglionic AChR; muscle AChR; amphiphysin; VGKC; paraproteins Ganglionic AChR; VGKC; CRMP-5; muscle AChR Ganglionic AChR; VGCC (N>P/Q-type); CRMP-5; ANNA-1; striational; VGKC; muscle AChR; GAD65 VGCC (P/Q>N-type); muscle AChR; striational; ganglionic AChR; AGNA-1/ANNA-4 Muscle AChR;... 1 980 ) Paraclinical findings Cranial MRI and CT typically show normal brain structures, but reveal abnormal soft tissues and calcification in the vestibular system and cochlear labyrinth Gadolinium enhancement may be seen in these structures in acute stages The pathology of CS shows chronic in ammation with lymphocytic in ltration in early stages, and neovascularization and scarring in late stages in. .. tumor free during a two-year follow up Anti-VGKC antibodies in the serum of patients with LE bind to α-dendrotoxinsensitive potassium channels including the Kv1.1, 1.2, and 1.6 subtypes that are expressed throughout the brain and PNS It is not completely understood why the clinical phenotype includes limbic and autonomous symptoms without PNS hyperexcitability (neuromyotonia) in these patients In immunohistochemical... effective in panuveitis, and can be used in combination with steroids and hydroxychloroquine (Zajicek, 2000) Recent data suggest that refractory neurosarcoidosis may also be successfully treated with agents possessing antitumor necrosis factor α (TNF-α) activity such as thalidomide, pentoxyfilline and in iximab In iximab is a chimeric human-murine antibody directed against TNF-α, which holds great promises in. .. cancer than in anti-Hu positive patients, but even in the anti-Hu negative cases the overall prognosis is poor The presentation of autoimmune form is both clinically and radiologically indistinguishable from the paraneoplastic variant, and usually is associated with the presence of anti-VGKC antibodies The clinical symptoms of LE include subacute development of short-term memory loss, complex partial,... generalized tonic-clonic or other seizure types, behavioral abnormalities and confusion T2weighted and FLAIR MRI images usually demonstrate hyperintense lesions in the mesial temporal lobe involving the hippocampus and amygdale (Fig 18. 1) Postgadolinium enhancement may be seen on T1-weighted imaging The histopathology includes perivascular in ammatory in ltrates, neuronal loss and gliosis in the mesio-temporal . out of nine patients with RE (Watson et al., 2005). These antibodies blocked acetylcholine-induced increase in intracellular free calcium and inhibited 125 I-α-bungarotoxin bind- ing in cells. 2005; Chiapparini et al., 2003). Initially, a unilateral enlargement of CSF compart- ments, particularly in the peri-insular/peri-Sylvian region, with T2-weighted and FLAIR hyperintensity and. disease. Rinsho Shinkeigaku, 32, 191 8. Zettinig, G., Asenbaum, S., Fueger, B.J. et al. 2003. Increased prevalence of subclinical brain perfusion abnormalitis in patients with autoimmune thyroi- ditis: