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Amyloid in neurosurgical and neurological practice
Journal of Clinical Neuroscience 13 (2006) 159–167 www.elsevier.com/locate/jocn
Review
Amyloid in neurosurgical and neurological practice G. Samandouras a
a,*
, P.J. Teddy c, T. Cadoux-Hudson a, O. Ansorge
b
Department of Neurosurgery, The Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, England b Department of Neuropathology, The Radcliffe Infirmary, Oxford, England c Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia Received 17 January 2005; accepted 16 May 2005
Abstract The amyloidoses are a diverse group of diseases characterized by the deposition of specific proteins with distinct affinity to the dye Congo red, collectively called amyloid. The amyloidogenic proteins have acquired an abnormal, highly ordered, b-pleated sheet configuration with a propensity to self-aggregate. The amyloid may be distributed in different organs with a remarkable diversity. Two broad categories of amyloidoses are recognised: The systemic (consisting of the primary or light chain form, the secondary or reactive form and the familial or hereditary form) and the localised that target specific organs. A tropism of amyloid proteins to the neural tissue produces certain patterns of central nervous system diseases: cerebral amyloid angiopathy, a substrate of spontaneous intracerebral haemorrhage; mature neuritic plaques found in Alzheimer disease and a subset of prion diseases; a topographically restricted accumulation of extracellular proteins giving rise to tumour-mimicking masses, the amyloidomas; and finally, spinal extradural amyloid collections that occasionally are found in the context of rheumatoid arthritis. In this review article we present original illustrative cases of amyloid diseases of the central nervous system that may be encountered in neurosurgical and neurological practice. Molecular aspects and clinical management problems are discussed. 2005 Elsevier Ltd. All rights reserved. Keywords: Amyloid; Amyloidoses; Amyloid angiopathy; Amyloidoma; Plague; Congo red
1. Amyloid in neurosurgical and neurological practice The amyloidoses are a group of disorders sharing the pathological hallmark of systemic or localised amyloid deposition. In this review we describe several amyloidrelated disorders and present illustrative clinical cases that are likely to be encountered in neurosurgical and neurological practice. 1.1. Terminology and pathogenesis The term amyloid was coined by Virchow. He believed that amyloid was composed of a polysaccharide resembling starch (altkom in Greek).
*
Corresponding author. Tel.: +44 0 1865 311188; fax: +44 0 1865 224868. E-mail address: [email protected] (G. Samandouras). 0967-5868/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2005.05.009
We now know that amyloid can be formed by many and, in the primary sequence, unrelated proteins. The term is used generically to indicate a specific conformational abnormality in a protein deposit. The key element for amyloidogenesis is a protein misfolding into a highly organised beta pleated sheet (‘‘zigzag’’) conformation that promotes self aggregation. These specific and highly insoluble aggregates can be identified by labelling with Congo-red dye that has a high affinity for the beta-sheet motif, resulting in a red signal under brightfield microscopy and yellow-green birefringence under polarised light (Fig. 1). Ultrastructurally, amyloid consists of rigid, linear, non-branching fibres of indefinite length but with a distinct diameter of 7.5 to 10 nm. Each fibre is formed from four to six interlacing, contiguous polypeptide chains, called protofilaments (Fig. 1).1 Amyloid formation is a dynamic and potentially reversible process. Whether a protein becomes amyloidogenic is determined by several factors involving the protein itself or its environment.2 For example, a wild type protein
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(alpha-synuclein inclusions) and Huntington’s disease (polyglutamine inclusions).3 1.2. Clinical syndromes and classification Exactly how amyloidogenic proteins cause clinical disease remains uncertain, although theories include physical interference with normal cellular and organ function, mass effect (e.g. in tumour-like amyloidomas), production of soluble toxic intermediates, induction of inflammatory response, or overload of the ubiquitin-proteasome (UPS) system. Systemic (generalised) and tissue-specific (localised) are the two main forms of amyloidosis.
Fig. 1. The amyloid fibril. The ultrastructure of the amyloid fibril consists of four to six protofilaments allowing regular intercalation of Congo red dye. Adapted with permission from reference 2. Copyright 2003 Massachusetts Medical Society. All rights reserved.
may have the intrinsic propensity to become unstable over time (e.g. senile transthyretin amyloidosis and late onset sporadic Creutzfeldt-Jakob disease, CJD). Such propensity may be exacerbated by persistently high concentrations of the respective protein (e.g. alpha-microglobulin in longterm haemodialysis patients) and changes in pH. Furthermore, a wild-type protein may be cleaved into an amyloidogenic fragment (e.g. the amyloid-precursor protein into beta-amyloid in Alzheimer’s disease, AD), or a mutation can cause the exchange of a single amino acid or a premature stop codon, facilitating misfolding of the affected protein (e.g. some inherited prion diseases or familial cerebral angiopathies). Classically, amyloid was considered to be a purely extracellular protein deposit. However, recent experimental evidence has widened the concept of amyloidoses to include intracellular protein aggregates, particularly in the field of neurodegenerative diseases such as Parkinson’s disease
1.2.1. Systemic amyloidoses The primary or light chain form, the secondary or reactive form and the familial or hereditary form are the commonest types of systemic amyloidosis. In each type, different precursor proteins give rise to the amyloid fibres.4 The immunoglobulin light chain (AL) amyloidosis resulting from k or j chain precursor proteins can affect the heart, liver, autonomic and peripheral nervous system. Amyloid A protein is the precursor in secondary (AA) amyloidosis seen in chronic inflammation (rheumatoid arthritis) or infection (tuberculosis, TB). In the familial transthyretin-associated amyloidosis (ATTR), a mutation in the transport protein transthyretin produced in the liver and the choroid plexus, produces in midlife peripheral and autonomic neuropathy and cardiomyopathy.2,4 The most common clinical forms of systemic amyloidoses are summarised in Table 1. 1.2.2. Localised amyloidoses Localised deposition of amyloid can involve a variety of tissues including but not limited to endocrine tissues (e.g. medullary carcinoma of the thyroid, insulinoma, tumours of the pituitary). Such deposits may be found in plasmocytomas, and they may be conjunctival, laryngeal, or renal involvement.5 Varieties of amyloidosis are limited to specific organs including the skin, the myocardium, the respiratory tract, the urinary tract and the cerebral tissue.5 1.3. Amyloidosis and the central nervous system It is useful for the neurosurgeon and neurologist to understand the pathophysiology of formation and deposi-
Table 1 Common clinical forms of systemic amyloidoses Common systemic amyloidoses and their amyloidogenic proteins Type
Precursor protein
Clinical manifestations
AL (Primary) AA (Secondary) ATTR (Familial) Other familial types
k or j light chains Amyloid A protein Abnormal transthyretin Apo A-I, gelsolin, fibrinogen A a, lysozyme
Cardiomyopathy, hepatomegaly, proteinuria, autonomic and peripheral neuropathy Underlying inflammatory disorder, hepatosplenomegaly, renal insufficiency, proteinuria Peripheral and autonomic neuropathies, cardiomyopathies Polyneuropathies, nephropathies, hypertension, hepatomegaly
Modified from reference 4.
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tion of the common pathological substrate, amyloid. In the brain, the b-pleated sheet fibril deposits can be found in four distinct forms.5 1. Amyloid angiopathy affecting arteries and arterioles, adventitia of veins and basement membrane of capillaries. Amyloid angiopathy often accompanies classical AD pathology, but also may occur in isolation and in the context of several inherited syndromes. 2. Extracellular amyloid ‘plaques’ classically consisting of a central core and a diffuse rim of amyloid fibrils enmeshed with degenerative neuritic material, activated microglia and astrocytes. The prototype is the mature neuritic plaque composed of beta-A4 amyloid in AD. However, a range of inherited neurodegenerative diseases such as Familial British Dementia and a subset of prion diseases may show morphologically similar, but molecularly distinct plaques. 3. Extracellular amyloid ‘tumours’, unlike ‘plaques’ a topographically very restricted massive accumulation of amyloid. 4. Intracellular amyloidosis, where microaggregates of misfolded protein develop in neuronal nuclei (e.g. polyglutamine diseases), soma (neurofibrillary tangles of tauopathies such as AD or Pick’s disease, and Lewy bodies in Parkinson’s disease) or neurites. The deposition of amyloid peptides in the neural tissues of the brain and spinal cord can produce a variety of clinical problems that may be encountered in neurosurgical and neurological practice (Table 2). 1. In the brain, amyloid angiopathy is a common substrate of spontaneous intracranial haemorrhage in the elderly. 2. The rare amyloidoma, a large, localised aggregation of intracerebral amyloid may closely mimic intra-axial tumours. 3. Amyloid underlies not only AD but also other neurodegenerative disorders presenting as dementias (e.g. CJD and other spongiform encephalopathies (prion diseases)). 4. In the spine, close association is observed between amyloidosis and rheumatoid arthritis while intramedullary amyloidomas may present as tumour-like lesions. In the following section we present four original cases from our institution to illustrate the four main categories
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of amyloidosis outlined above and discuss the pathogenic, diagnostic and therapeutic aspects of each. 1.3.1. Amyloid angiopathy causing spontaneous intracerebral haemorrhage: Original illustrative case A 71-year-old man presented with acute onset of headaches and vomiting. Two days later he became drowsy and dysphasic. CT scan of his brain revealed a 5 · 3 cm, left frontal intracerebral haemorrhage extending from the anterior frontal gyrus to the frontal horn of the lateral ventricle causing a 5 mm midline shift. (Fig. 2A) A cerebral angiogram demonstrated no evidence of aneurysm or AVM. At left frontal craniotomy the haematoma was evacuated uneventfully leading to an excellent recovery. Surgical specimens consisting of haemorrhagic brain tissue revealed the presence of amyloid angiopathy due to deposits of betaA4 peptide in the vessel walls. No Alzheimer plaques or neurofibrillary tangles were noted (Figs. 2B–D). Cerebral amyloid angiopathy (CAA) is a well-recognised cause of non-traumatic lobar haemorrhage in patients over 70 years; other manifestations include ischemic lesions and dementia.6 In the sporadic CAA and in CAA related to sporadic AD, there is a characteristic beta-A4 deposition.6 The amyloid peptide deposits in the media of the small and medium size arteries possibly have a direct toxic effect on the smooth muscle cells.7 Although most patients recover from the initial lobar haemorrhage, recurrences are common and substantially increase morbidity and mortality.8,9 The annual risk of recurrent haemorrhage is 10.5%.10,11 O’Donnell examined the apolipoprotein E genotype as a risk factor for recurrent lobar haemorrhage. The three common allelic forms of apolipoprotein E are designated e2, e3 (the most common) and e4.11 The expression of e2 or e4 alleles increases the vasculopathic effects of amyloid in cerebral vessels.10,11 Carriers of the e2 or e4 allele had a two year recurrence of 28% compared with only 10% for patients with the common apolipoprotein E genotype. Cerebral angiography very rarely reveals vessel abnormalities.12 No laboratory investigation performed on serum or CSF is diagnostic of amyloid angiopathy. Definitive diagnosis is based solely on the histological confirmation of severe, cerebral amyloid angiopathy and the absence of other causes of lobar haemorrhage following standard laboratory and imaging investigations.13
Table 2 Amyloid-related clinical problems that may be encountered in neurosurgical and neurological practice Amyloidoses that can affect the central nervous system Location
Pathology
Clinical manifestations
Brain Brain Brain Spine
Amyloid angiopathy Intracerebral amyloidoma Sporadic degenerative dementias Amyloid deposition in the rheumatoid spine
Spontaneous intracerebral haemorrhage Tumour-mimicking lesion Dementias that are very occasionally referred for brain biopsies Compression of spinal cord or nerve roots
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Fig. 2. Cerebral haemorrhage due to amyloid angiopathy. (A) Axial CT scan of the brain demonstrates a left frontal haemorrhage with intraventricular haemorrhage (B) the biopsy consists of necrotic and haemorrhagic brain tissue; the vessels contain pale eosinophilic amorphous material which stains strongly for beta-A4 amyloid (C,D). (B) H&E, (C, D) beta A4 immunohistochemistry (original magnifications ·200 (B,C), ·400 (D).
1.3.2. Intracerebral amyloidoma mimicking intra-axial tumour: Original illustrative case A 61-year-old woman presented with a 2-year history of decreased vision and abnormal visual fields progressing slowly to right homonymous hemianopia. An MRI scan revealed a left temporo-occipital intrinsic lesion associated with minimal mass effect (Figs. 3A–C). She was initially reluctant to undergo surgery. The lesion did not appear to change on repeated imaging over a period of 15 months. Since the imaging features were non-diagnostic and there was progression in visual deficit she agreed to proceed to a diagnostic biopsy. Tissue obtained using image-guided craniotomy revealed the presence of localised, massive, vascular and parenchymal amyloid fibres in keeping with intracerebral amyloidoma (Figs. 3D–I). This was associated with a few B-lymphocytes but there was no evidence of plasmacytoma or other intracerebral lymphoma. Further investigations were performed to exclude possible systemic amyloidosis. The serum free light chains assay was completely normal and paraproteins were absent in serum and urine. The SAP scan, a scintigraphic imaging method that can confirm the presence and distribution of amyloid, through binding of the normal serum SAP protein to amyloid, was negative
for visceral amyloid deposits. Organ function biochemistry was normal and echocardiogram and ECG were unremarkable. The patient was referred to the National Amyloidosis Centre where it was felt that this particular case most likely represented an AL amyloidosis with a small clone of intracerebral B-cells secreting amyloidogenic light chains. Localised amyloidomas have been reported in extracranial tissues including lung, bone, skin, lymph nodes, and gastrointestinal and urinary tracts.14 Intracranial amyloidomas can involve the cerebrum, pituitary gland, jugular foramen and the facial bones.14–18 Intracerebral amyloidoma is a previously described but poorly understood entity in which, usually in the absence of systemic amyloidosis, extracellular amyloid deposits accumulate in the brain tissue giving the appearance of an intrinsic lesion that may be interpreted as tumour. Saltykow first described intracerebral amyloidomas in the cortex of a psychiatric patient almost 70 years ago19. Further reports appeared later in the literature with 14 cases being published so far.20,21 The imaging features are not diagnostic but are not characteristic for tumour either. On CT imaging the lesion appears as low density areas with or without contrast. On
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Fig. 3. Cerebral amyloidoma. (A) A plain CT of the brain demonstrates a left posterior parieto–occipital low density lesion (arrow). (B) The lesion has a high signal on T1-weighted MRI and does not enhance following administration of gadolinium (arrow). (C) On T2-weighted MRI the lesion has a high signal with some sparing of the sulci producing a ‘‘serpentine’’ appearance (arrow). (D) Amyloid appears as a cloudy blue mass on intraoperative smear preparations (methylene blue); on H&E it is evident as pale eosinophilic intraparenchymal globules (E,G), sometimes associated with a few small lymphocytes (G). The globules (E,H) and some thickened vessels (F,I) are very strongly Congo red positive (D–I, original magnification ·200). H&E (D,G) and Congo red (E,F,H,I) stain. Brightfield microscopy (D–G) and polarised light microscopy (H,I).
MRI the lesion can have variable appearance and can be isointense, hyperintense or hypointense.20 The lesion has little or no mass effect, and in our case did not enhance following administration of gadolinium. Amyloidomas display little or no change in serial imaging. The management of intracerebral amyloidomas varies with treatments ranging from observation only to surgical excision if the amyloid mass is enlarging or the symptoms are progressing. Townsend, who reported two cases of intracerebral amyloidoma, suggested surgical excision with further operation in amyloidoma recurrence.22 The role of intrathecal steroids or chemotherapy is under investigation. In the absence of further progressive neurology and with the uncertainty of optimal management of these cases our patient is simply receiving regular clinical follow-ups with serial imaging.
1.3.3. Sporadic degenerative dementia referred for brain biopsy: Original illustrative case A 73-year-old woman presented with an insidious intellectual decline 6 months prior to her admission. Her symptoms started after a trip to Spain when she developed a ‘‘flu-like’’ illness followed by progressive unsteadiness on her feet and memory problems. Neurologic examination revealed difficulty in word finding, pronunciation and enunciation. She had myoclonus in her arms and dysphagia. Her gait was hesitant and within a period of few weeks she required the assistance of two to walk. Neuropsychological assessment showed global impairment with executive/attentional dysfunction suggesting pathology within the fronto-striatal system. MRI scan of the brain showed cortical atrophy with pronounced subarachnoid spaces (Fig. 4A) while EEG showed slow wave
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Fig. 4. Creutzfeldt-Jakob disease. (A) T2-weighted MRI scan demonstrates extensive cortical atrophy with pronounced subarachnoid spaces. (B) Following a small craniectomy by joining three burr-holes the exposed brain showed atrophic changes with accumulation of subarachnoid fluid and gliotic changes. The biopsy revealed multifocal, partially confluent vacuoles in the cerebral cortex (C, H&E) with strong perivacuolar and dot-like prion protein amyloid deposition (D, KG9 antibody). (Original magnifications ·400).
activity over the fronto-temporal regions bilaterally. The patient was referred to the neurosurgical service for a brain biopsy. Under general anaesthesia and using disposable instruments a free bone flap was raised. Inspection of the brain showed prominent subarachnoid spaces suggesting atrophy. (Fig. 4B) A 0.5 cm cortical sample was excised taking extra care to avoid disturbance of the cortical architecture. Pathologic examination revealed numerous, partially confluent vacuoles in the cortex giving an overall spongiform appearance. (Figs. 4C–D) Immonohistochemical staining for prion protein with antibody KG9 was positive and showed a characteristic perivacuolar and dot-like pattern. (Figs. 4C–D) No prion protein plaques were detected. The histological picture was consistent with sporadic CJD. Western blot analysis of frozen tissue confirmed this. It showed the characteristic prion protein PrP isotype 2A. The patient died in a nursing home one month after her admission.
Clinical criteria are usually sufficient for the diagnosis of most dementias. The combination of dementia with cerebellar signs or myoclonus can raise the suspicion of CJD. Akinetic mutism and periodic sharp wave complexes on EEG appear to be more specific for CJD. CSF analysis can provide sensitive and specific markers for the disease. In a prospective study of 250 patients with possible CJD, the CSF determinations of the 14-3-3 and tau proteins were proven valuable tools in CJD diagnosis.23 Sensitivities for the 14-3-3 and tau proteins in CSF were 100% and 87% respectively and specificities were 93% and 98% respectively. Detection of CSF tau protein had the highest positive predictive value while detection of CSF 14-3-3 protein had the highest negative predictive value.23 Although every effort should be undertaken to avoid biopsy of a patient with possible CJD disease, atypical presentation or imaging features, on rare occasions, may require a diagnostic biopsy. The neurosurgeon is likely to be called for an opinion or to confirm the diagnosis, pref-
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erably by an open block biopsy. Special precautions when handling the neurosurgical instruments and biopsy material are necessary. Information for UK guidelines can be found at the UK Department of Health website.24 Infection Control Guidelines for transmissible spongiform encephalopathies were published in 1999 and can be found at the WHO website.25 Prions, the transmissible particles that are devoid of nucleic acid and are composed of a modified protein (PrPSc) can cause not only infectious but also genetic and sporadic disorders. Fatal spongiform encephalopathies including bovine spongiform encephalopathy, scrapie of sheep and CJD are notable prion diseases. The key mechanism is the transition of the normal cellular PrP (PrPC) to the abnormal PrPSc through a post-translational process during which the PrPC acquires the high b-sheet content.26 The main differential diagnosis in dementias sufficiently unusual to require a brain biopsy, is an atypical presentation of AD. The amyloid observed in amyloid angiopathy is often identical to the b-amyloid observed in AD although most patients with CAA do not have AD. A population based study suggested that individuals with both CAA and AD had substantially worse cognitive performance during life compared with patients with AD alone, supporting the possibility of a synergistic relationship of the two entities.27,28
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In addition, AD is characterized by intracellular fibril deposition. Kidd described intracellular paired helical filaments that displayed green polarization after staining with Congo red.29 These fibrils consist mainly of the microtubule-associated protein tau, and are most commonly seen in AD although they are not specific for the disease. They are 12 to 12.5 nm wide and have a helical periodic twist of 80 nm.5 In the spongiform encephalopathies of Kuru and CJD, microtubules with a diameter of 10 to 13 nm and transverse periodicity may be demonstrated.5,30 Current research efforts aim toward understanding the folding pathways of the prion proteins since it appears that the propagation of spongiform encephalopathies requires the conversion of the PrPC to the misfolded oligomeric form, PrPSc.31 1.3.4. Amyloid and the spine: Original illustrative case A 75-year-old woman presented with a 16 year history of progressive lower limb stiffness. Neurological examination showed markedly increased tone in her lower limbs with brisk reflexes. MRI of her cervical spine showed extensive pannus formation with a cystic lesion resembling a toadstool causing anterolateral compression of the medulla and the upper cervical cord (Figs. 5A–B). A mild erosion of the posterior cortical margin of C2 was also present but there was no instability on flexion/extension films.
Fig. 5. Spinal amyloidosis. (A) Sagittal T2-Weighted MRI demonstrates a high signal lesion anterior to the lower medulla and higher spinal cord. (B) Axial view through the lesion shows an extra-axial lesion compressing antero-laterally the upper cervical cord. The biopsy tissue consists of fibrocartilaginous material with diffuse and globular amyloid deposits (C, H&E), (D, Congo red brightfield), (E, Congo red polarised light) (original magnifications ·200).
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She underwent a C1/C2 laminectomy with excision of the cystic mass. Pathological examination showed degenerative ligamentous tissue with considerable deposition of amyloid confirmed by Congo red stain. (Figs. 5C–E) Routine laboratory investigations, bone marrow scan, SAP scan and cardiac echo were normal. There was no evidence of systemic amyloidosis. Immunohistochemistry studies excluded AA and ATTR amyloidosis but not the immunoglobulin light chain form of the disease. Although immunostaining with light chain antisera was negative this was still consistent with AL amyloidosis as in this form only half the cases are stainable with commercial antisera. Spinal amyloidomas have been described in the literature and are usually confined to the extradural space with or without bony involvement.14,32 The thoracic and cervical spine are most commonly involved. The extradural amyloid mass produces symptoms or deficits according to its location and most commonly spans one or two vertebral levels. Axial pain, paraparesis and sensory level predominate in the usually acute clinical presentation. Bony involvement including not only the arch but also the vertebral body has been described. The slow growing lesion may involve soft tissues and appear calcified.32,33 The differential diagnosis includes primary or metastatic bone tumour, plasmocytoma or granulomatous lesions.14 Imaging features demonstrate hypo- or iso-intensity in both T1-weighted images and iso- or hyper-intensity in T2-weighted MRI.32,34,35 Histological examination of human intervertebral discs taken from autopsies as well as from surgical procedures demonstrated the presence of lipofuscin and amyloid deposition.36 Although the clinical significance of this observation is not determined at present, it is obvious that the presence of amyloid is a sign of ageing in the intervertebral disc as well as in other tissues. Surgical excision of spinal amyloid collections may release the mass effect exerted upon the spinal cord or nerve roots, control the axial or limb pain, and improve neurological deficits.14,32 2. Conclusions The neurosurgeon and neurologist will encounter in his/ her practice diseases of the brain and spine caused by amyloid deposits. Spontaneous lobar haemorrhages in the elderly are common examples but the tumour-mimicking intracerebral and spinal amyloidomas may also present and should be borne in mind as early diagnosis might significantly affect management and prognosis. References 1. Glenner GC. Amyloid deposits and amyloidosis. Part I. N Engl J Med 1980;302:1283–92. 2. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349:583–96. 3. Selkoe DJ. Folding proteins in fatal ways. Nature 2003;426:900–4.
4. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898–909. 5. Glenner GC. Amyloid deposits and amyloidosis. Part II. N Engl J Med 1980;302:1333–43. 6. Revesz T, Ghiso J, Lashley T, et al. Cerebral amyloid angiopathies: A pathologic, biochemical, and genetic view. Journal of Neuropathology and Experimental Neurology 2003;62:885–98. 7. Yamaguchi H, Yamazaki T, Lemere CA, Frosch MP, Selkoe DJ. Beta amyloid is focally deposited within the outer membrane in the amyloid angiopathy of Alzheimer’s disease: an immunoelectron microscopic study. Am J Pathol 1992;141:249–59. 8. Passero S, Burgalassi L, D’Andrea P, Batisstini N. Recurrence of bleeding in patients with primary intracerebral haemorrhage. Stroke 1995;26:1189–92. 9. Nean JP, Ingrand P, Conderq C, et al. Recurrent intracerebral haemorrhage. Neurology 1997;49:106–13. 10. Qureshi AI, Tuhrim S, Broderick JP, Butjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–60. 11. O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral haemorrhage. N Engl J Med 2000;342:240–5. 12. Wagle WA, Smith TW, Weiner M. Intracerebral haemorrhage caused by cerebral amyloid angiopathy: radiographic-pathologic correlation. AJNR Am J Neuroradiol 1984;5:171–6. 13. Case records of the Massachusetts General Hospital. Case 22-1996. N Engl J Med 1996; 335:189–196. 14. Suri VS, Tatke M, Kumar S, Gupta V. Amyloidoma of the thoracic spine. J Neurosurg (Spine) 2001;94:299–301. 15. Kuratsu J, Matsukado Y, Miura M. Prolactinoma of pituitary with associated amyloid-like substances. Case report. J Neurosurg 1983;59:1067–70. 16. Mori H, Mori S, Saitoh Y, et al. Growth-hormone producing pituitary adenoma with crystal-like amyloid immunochemically positive for growth hormone. Cancer 1985;55:96–102. 17. Matsumoto T, Tani E, Maeda Y, et al. Amyloidomas in the cerebellopontine angle and jugular foramen. Case Report. J Neurosurg 1985;62:592–6. 18. O’Brien TJ, McKelvie PA, Vrodos N. Bilateral trigeminal amyloidoma: an unusual case of trigeminal neuropathy with review of the literature. J Neurosurg 1994;81:780–3. 19. Saltykow S. Zur Frage des lokalen Amyloids der Hirngefasse. Bemerkung zu dem Aufsatz von Morgenstern. Virchows Arch (Pathol Anat) 1935;295:590. 20. Gandhi D, Wee R, Goyal M. CT and MR imaging of intracerebral amyloidoma: Case report and review of the Literature. AJNR Am J Neuroradiol 2003;24:519–22. 21. Spaar FW, Goebel HH, Volles E, Wickboldt J. Tumor-like amyloid formation (amyloidoma) in the brain. J Neurol 1981;224:171–82. 22. Townsend JJ, Tomiyasu U, MacKay A, Wilson CB. Central nervous system amyloidosis presenting as a mass lesion. Report of two cases. J Neurosurg 1982;56:439–42. 23. Everbroeck BV, Quoilin S, Boons J, Martin JJ, Cras PP. A prospective study of CSF markers in 250 patients with possible Creutzfeldt–Jakob disease. J Neurol Neurosurg Psychiatry 2003;74: 1210–4. 24. http://www.dh.gov.uk/assetRoot/04/08/27/21/04082721.PDF. 25. http://www.who.int/emc-documents/tse/whocdscsraph2003c.html. 26. Prusiner SB. Prions. Proc Natl Acad Sci USA 1998;95:13363–83. 27. Greenberg SM. Cerebral amyloid angiopathy and dementia. Neurology 2002;58:1578–88. 28. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 2002;58:1629–34. 29. Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 1963;197:192–3. 30. Chou SM, Martin JD. Kuru plaques in a case of Creutzfeldt-Jacob disease. Acta Neuropathol (Berl) 1971;17:150–5.
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34. Dickman CA, Sonntag VK, Johnson P, Medina M. Amyloidoma of the cervical spine: a case report. Neurosurgery 1988;22:419–22. 35. Meyers SP, Mullins KJ, Kazee AM. Unifocal primary amyloidoma of the spine causing compression of the cervical spinal cord: MR findings. J Comput Assist Tomogr 1996;20:592–3. 36. Yasuma T, Arai K, Suzuki F. Age-related phenomena in the lumbar intervertebral discs. Lipofuscin and amyloid deposition. Spine 1992;17: 1194–8.
Review
Amyloid in neurosurgical and neurological practice G. Samandouras a
a,*
, P.J. Teddy c, T. Cadoux-Hudson a, O. Ansorge
b
Department of Neurosurgery, The Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, England b Department of Neuropathology, The Radcliffe Infirmary, Oxford, England c Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia Received 17 January 2005; accepted 16 May 2005
Abstract The amyloidoses are a diverse group of diseases characterized by the deposition of specific proteins with distinct affinity to the dye Congo red, collectively called amyloid. The amyloidogenic proteins have acquired an abnormal, highly ordered, b-pleated sheet configuration with a propensity to self-aggregate. The amyloid may be distributed in different organs with a remarkable diversity. Two broad categories of amyloidoses are recognised: The systemic (consisting of the primary or light chain form, the secondary or reactive form and the familial or hereditary form) and the localised that target specific organs. A tropism of amyloid proteins to the neural tissue produces certain patterns of central nervous system diseases: cerebral amyloid angiopathy, a substrate of spontaneous intracerebral haemorrhage; mature neuritic plaques found in Alzheimer disease and a subset of prion diseases; a topographically restricted accumulation of extracellular proteins giving rise to tumour-mimicking masses, the amyloidomas; and finally, spinal extradural amyloid collections that occasionally are found in the context of rheumatoid arthritis. In this review article we present original illustrative cases of amyloid diseases of the central nervous system that may be encountered in neurosurgical and neurological practice. Molecular aspects and clinical management problems are discussed. 2005 Elsevier Ltd. All rights reserved. Keywords: Amyloid; Amyloidoses; Amyloid angiopathy; Amyloidoma; Plague; Congo red
1. Amyloid in neurosurgical and neurological practice The amyloidoses are a group of disorders sharing the pathological hallmark of systemic or localised amyloid deposition. In this review we describe several amyloidrelated disorders and present illustrative clinical cases that are likely to be encountered in neurosurgical and neurological practice. 1.1. Terminology and pathogenesis The term amyloid was coined by Virchow. He believed that amyloid was composed of a polysaccharide resembling starch (altkom in Greek).
*
Corresponding author. Tel.: +44 0 1865 311188; fax: +44 0 1865 224868. E-mail address: [email protected] (G. Samandouras). 0967-5868/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2005.05.009
We now know that amyloid can be formed by many and, in the primary sequence, unrelated proteins. The term is used generically to indicate a specific conformational abnormality in a protein deposit. The key element for amyloidogenesis is a protein misfolding into a highly organised beta pleated sheet (‘‘zigzag’’) conformation that promotes self aggregation. These specific and highly insoluble aggregates can be identified by labelling with Congo-red dye that has a high affinity for the beta-sheet motif, resulting in a red signal under brightfield microscopy and yellow-green birefringence under polarised light (Fig. 1). Ultrastructurally, amyloid consists of rigid, linear, non-branching fibres of indefinite length but with a distinct diameter of 7.5 to 10 nm. Each fibre is formed from four to six interlacing, contiguous polypeptide chains, called protofilaments (Fig. 1).1 Amyloid formation is a dynamic and potentially reversible process. Whether a protein becomes amyloidogenic is determined by several factors involving the protein itself or its environment.2 For example, a wild type protein
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(alpha-synuclein inclusions) and Huntington’s disease (polyglutamine inclusions).3 1.2. Clinical syndromes and classification Exactly how amyloidogenic proteins cause clinical disease remains uncertain, although theories include physical interference with normal cellular and organ function, mass effect (e.g. in tumour-like amyloidomas), production of soluble toxic intermediates, induction of inflammatory response, or overload of the ubiquitin-proteasome (UPS) system. Systemic (generalised) and tissue-specific (localised) are the two main forms of amyloidosis.
Fig. 1. The amyloid fibril. The ultrastructure of the amyloid fibril consists of four to six protofilaments allowing regular intercalation of Congo red dye. Adapted with permission from reference 2. Copyright 2003 Massachusetts Medical Society. All rights reserved.
may have the intrinsic propensity to become unstable over time (e.g. senile transthyretin amyloidosis and late onset sporadic Creutzfeldt-Jakob disease, CJD). Such propensity may be exacerbated by persistently high concentrations of the respective protein (e.g. alpha-microglobulin in longterm haemodialysis patients) and changes in pH. Furthermore, a wild-type protein may be cleaved into an amyloidogenic fragment (e.g. the amyloid-precursor protein into beta-amyloid in Alzheimer’s disease, AD), or a mutation can cause the exchange of a single amino acid or a premature stop codon, facilitating misfolding of the affected protein (e.g. some inherited prion diseases or familial cerebral angiopathies). Classically, amyloid was considered to be a purely extracellular protein deposit. However, recent experimental evidence has widened the concept of amyloidoses to include intracellular protein aggregates, particularly in the field of neurodegenerative diseases such as Parkinson’s disease
1.2.1. Systemic amyloidoses The primary or light chain form, the secondary or reactive form and the familial or hereditary form are the commonest types of systemic amyloidosis. In each type, different precursor proteins give rise to the amyloid fibres.4 The immunoglobulin light chain (AL) amyloidosis resulting from k or j chain precursor proteins can affect the heart, liver, autonomic and peripheral nervous system. Amyloid A protein is the precursor in secondary (AA) amyloidosis seen in chronic inflammation (rheumatoid arthritis) or infection (tuberculosis, TB). In the familial transthyretin-associated amyloidosis (ATTR), a mutation in the transport protein transthyretin produced in the liver and the choroid plexus, produces in midlife peripheral and autonomic neuropathy and cardiomyopathy.2,4 The most common clinical forms of systemic amyloidoses are summarised in Table 1. 1.2.2. Localised amyloidoses Localised deposition of amyloid can involve a variety of tissues including but not limited to endocrine tissues (e.g. medullary carcinoma of the thyroid, insulinoma, tumours of the pituitary). Such deposits may be found in plasmocytomas, and they may be conjunctival, laryngeal, or renal involvement.5 Varieties of amyloidosis are limited to specific organs including the skin, the myocardium, the respiratory tract, the urinary tract and the cerebral tissue.5 1.3. Amyloidosis and the central nervous system It is useful for the neurosurgeon and neurologist to understand the pathophysiology of formation and deposi-
Table 1 Common clinical forms of systemic amyloidoses Common systemic amyloidoses and their amyloidogenic proteins Type
Precursor protein
Clinical manifestations
AL (Primary) AA (Secondary) ATTR (Familial) Other familial types
k or j light chains Amyloid A protein Abnormal transthyretin Apo A-I, gelsolin, fibrinogen A a, lysozyme
Cardiomyopathy, hepatomegaly, proteinuria, autonomic and peripheral neuropathy Underlying inflammatory disorder, hepatosplenomegaly, renal insufficiency, proteinuria Peripheral and autonomic neuropathies, cardiomyopathies Polyneuropathies, nephropathies, hypertension, hepatomegaly
Modified from reference 4.
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tion of the common pathological substrate, amyloid. In the brain, the b-pleated sheet fibril deposits can be found in four distinct forms.5 1. Amyloid angiopathy affecting arteries and arterioles, adventitia of veins and basement membrane of capillaries. Amyloid angiopathy often accompanies classical AD pathology, but also may occur in isolation and in the context of several inherited syndromes. 2. Extracellular amyloid ‘plaques’ classically consisting of a central core and a diffuse rim of amyloid fibrils enmeshed with degenerative neuritic material, activated microglia and astrocytes. The prototype is the mature neuritic plaque composed of beta-A4 amyloid in AD. However, a range of inherited neurodegenerative diseases such as Familial British Dementia and a subset of prion diseases may show morphologically similar, but molecularly distinct plaques. 3. Extracellular amyloid ‘tumours’, unlike ‘plaques’ a topographically very restricted massive accumulation of amyloid. 4. Intracellular amyloidosis, where microaggregates of misfolded protein develop in neuronal nuclei (e.g. polyglutamine diseases), soma (neurofibrillary tangles of tauopathies such as AD or Pick’s disease, and Lewy bodies in Parkinson’s disease) or neurites. The deposition of amyloid peptides in the neural tissues of the brain and spinal cord can produce a variety of clinical problems that may be encountered in neurosurgical and neurological practice (Table 2). 1. In the brain, amyloid angiopathy is a common substrate of spontaneous intracranial haemorrhage in the elderly. 2. The rare amyloidoma, a large, localised aggregation of intracerebral amyloid may closely mimic intra-axial tumours. 3. Amyloid underlies not only AD but also other neurodegenerative disorders presenting as dementias (e.g. CJD and other spongiform encephalopathies (prion diseases)). 4. In the spine, close association is observed between amyloidosis and rheumatoid arthritis while intramedullary amyloidomas may present as tumour-like lesions. In the following section we present four original cases from our institution to illustrate the four main categories
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of amyloidosis outlined above and discuss the pathogenic, diagnostic and therapeutic aspects of each. 1.3.1. Amyloid angiopathy causing spontaneous intracerebral haemorrhage: Original illustrative case A 71-year-old man presented with acute onset of headaches and vomiting. Two days later he became drowsy and dysphasic. CT scan of his brain revealed a 5 · 3 cm, left frontal intracerebral haemorrhage extending from the anterior frontal gyrus to the frontal horn of the lateral ventricle causing a 5 mm midline shift. (Fig. 2A) A cerebral angiogram demonstrated no evidence of aneurysm or AVM. At left frontal craniotomy the haematoma was evacuated uneventfully leading to an excellent recovery. Surgical specimens consisting of haemorrhagic brain tissue revealed the presence of amyloid angiopathy due to deposits of betaA4 peptide in the vessel walls. No Alzheimer plaques or neurofibrillary tangles were noted (Figs. 2B–D). Cerebral amyloid angiopathy (CAA) is a well-recognised cause of non-traumatic lobar haemorrhage in patients over 70 years; other manifestations include ischemic lesions and dementia.6 In the sporadic CAA and in CAA related to sporadic AD, there is a characteristic beta-A4 deposition.6 The amyloid peptide deposits in the media of the small and medium size arteries possibly have a direct toxic effect on the smooth muscle cells.7 Although most patients recover from the initial lobar haemorrhage, recurrences are common and substantially increase morbidity and mortality.8,9 The annual risk of recurrent haemorrhage is 10.5%.10,11 O’Donnell examined the apolipoprotein E genotype as a risk factor for recurrent lobar haemorrhage. The three common allelic forms of apolipoprotein E are designated e2, e3 (the most common) and e4.11 The expression of e2 or e4 alleles increases the vasculopathic effects of amyloid in cerebral vessels.10,11 Carriers of the e2 or e4 allele had a two year recurrence of 28% compared with only 10% for patients with the common apolipoprotein E genotype. Cerebral angiography very rarely reveals vessel abnormalities.12 No laboratory investigation performed on serum or CSF is diagnostic of amyloid angiopathy. Definitive diagnosis is based solely on the histological confirmation of severe, cerebral amyloid angiopathy and the absence of other causes of lobar haemorrhage following standard laboratory and imaging investigations.13
Table 2 Amyloid-related clinical problems that may be encountered in neurosurgical and neurological practice Amyloidoses that can affect the central nervous system Location
Pathology
Clinical manifestations
Brain Brain Brain Spine
Amyloid angiopathy Intracerebral amyloidoma Sporadic degenerative dementias Amyloid deposition in the rheumatoid spine
Spontaneous intracerebral haemorrhage Tumour-mimicking lesion Dementias that are very occasionally referred for brain biopsies Compression of spinal cord or nerve roots
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Fig. 2. Cerebral haemorrhage due to amyloid angiopathy. (A) Axial CT scan of the brain demonstrates a left frontal haemorrhage with intraventricular haemorrhage (B) the biopsy consists of necrotic and haemorrhagic brain tissue; the vessels contain pale eosinophilic amorphous material which stains strongly for beta-A4 amyloid (C,D). (B) H&E, (C, D) beta A4 immunohistochemistry (original magnifications ·200 (B,C), ·400 (D).
1.3.2. Intracerebral amyloidoma mimicking intra-axial tumour: Original illustrative case A 61-year-old woman presented with a 2-year history of decreased vision and abnormal visual fields progressing slowly to right homonymous hemianopia. An MRI scan revealed a left temporo-occipital intrinsic lesion associated with minimal mass effect (Figs. 3A–C). She was initially reluctant to undergo surgery. The lesion did not appear to change on repeated imaging over a period of 15 months. Since the imaging features were non-diagnostic and there was progression in visual deficit she agreed to proceed to a diagnostic biopsy. Tissue obtained using image-guided craniotomy revealed the presence of localised, massive, vascular and parenchymal amyloid fibres in keeping with intracerebral amyloidoma (Figs. 3D–I). This was associated with a few B-lymphocytes but there was no evidence of plasmacytoma or other intracerebral lymphoma. Further investigations were performed to exclude possible systemic amyloidosis. The serum free light chains assay was completely normal and paraproteins were absent in serum and urine. The SAP scan, a scintigraphic imaging method that can confirm the presence and distribution of amyloid, through binding of the normal serum SAP protein to amyloid, was negative
for visceral amyloid deposits. Organ function biochemistry was normal and echocardiogram and ECG were unremarkable. The patient was referred to the National Amyloidosis Centre where it was felt that this particular case most likely represented an AL amyloidosis with a small clone of intracerebral B-cells secreting amyloidogenic light chains. Localised amyloidomas have been reported in extracranial tissues including lung, bone, skin, lymph nodes, and gastrointestinal and urinary tracts.14 Intracranial amyloidomas can involve the cerebrum, pituitary gland, jugular foramen and the facial bones.14–18 Intracerebral amyloidoma is a previously described but poorly understood entity in which, usually in the absence of systemic amyloidosis, extracellular amyloid deposits accumulate in the brain tissue giving the appearance of an intrinsic lesion that may be interpreted as tumour. Saltykow first described intracerebral amyloidomas in the cortex of a psychiatric patient almost 70 years ago19. Further reports appeared later in the literature with 14 cases being published so far.20,21 The imaging features are not diagnostic but are not characteristic for tumour either. On CT imaging the lesion appears as low density areas with or without contrast. On
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Fig. 3. Cerebral amyloidoma. (A) A plain CT of the brain demonstrates a left posterior parieto–occipital low density lesion (arrow). (B) The lesion has a high signal on T1-weighted MRI and does not enhance following administration of gadolinium (arrow). (C) On T2-weighted MRI the lesion has a high signal with some sparing of the sulci producing a ‘‘serpentine’’ appearance (arrow). (D) Amyloid appears as a cloudy blue mass on intraoperative smear preparations (methylene blue); on H&E it is evident as pale eosinophilic intraparenchymal globules (E,G), sometimes associated with a few small lymphocytes (G). The globules (E,H) and some thickened vessels (F,I) are very strongly Congo red positive (D–I, original magnification ·200). H&E (D,G) and Congo red (E,F,H,I) stain. Brightfield microscopy (D–G) and polarised light microscopy (H,I).
MRI the lesion can have variable appearance and can be isointense, hyperintense or hypointense.20 The lesion has little or no mass effect, and in our case did not enhance following administration of gadolinium. Amyloidomas display little or no change in serial imaging. The management of intracerebral amyloidomas varies with treatments ranging from observation only to surgical excision if the amyloid mass is enlarging or the symptoms are progressing. Townsend, who reported two cases of intracerebral amyloidoma, suggested surgical excision with further operation in amyloidoma recurrence.22 The role of intrathecal steroids or chemotherapy is under investigation. In the absence of further progressive neurology and with the uncertainty of optimal management of these cases our patient is simply receiving regular clinical follow-ups with serial imaging.
1.3.3. Sporadic degenerative dementia referred for brain biopsy: Original illustrative case A 73-year-old woman presented with an insidious intellectual decline 6 months prior to her admission. Her symptoms started after a trip to Spain when she developed a ‘‘flu-like’’ illness followed by progressive unsteadiness on her feet and memory problems. Neurologic examination revealed difficulty in word finding, pronunciation and enunciation. She had myoclonus in her arms and dysphagia. Her gait was hesitant and within a period of few weeks she required the assistance of two to walk. Neuropsychological assessment showed global impairment with executive/attentional dysfunction suggesting pathology within the fronto-striatal system. MRI scan of the brain showed cortical atrophy with pronounced subarachnoid spaces (Fig. 4A) while EEG showed slow wave
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Fig. 4. Creutzfeldt-Jakob disease. (A) T2-weighted MRI scan demonstrates extensive cortical atrophy with pronounced subarachnoid spaces. (B) Following a small craniectomy by joining three burr-holes the exposed brain showed atrophic changes with accumulation of subarachnoid fluid and gliotic changes. The biopsy revealed multifocal, partially confluent vacuoles in the cerebral cortex (C, H&E) with strong perivacuolar and dot-like prion protein amyloid deposition (D, KG9 antibody). (Original magnifications ·400).
activity over the fronto-temporal regions bilaterally. The patient was referred to the neurosurgical service for a brain biopsy. Under general anaesthesia and using disposable instruments a free bone flap was raised. Inspection of the brain showed prominent subarachnoid spaces suggesting atrophy. (Fig. 4B) A 0.5 cm cortical sample was excised taking extra care to avoid disturbance of the cortical architecture. Pathologic examination revealed numerous, partially confluent vacuoles in the cortex giving an overall spongiform appearance. (Figs. 4C–D) Immonohistochemical staining for prion protein with antibody KG9 was positive and showed a characteristic perivacuolar and dot-like pattern. (Figs. 4C–D) No prion protein plaques were detected. The histological picture was consistent with sporadic CJD. Western blot analysis of frozen tissue confirmed this. It showed the characteristic prion protein PrP isotype 2A. The patient died in a nursing home one month after her admission.
Clinical criteria are usually sufficient for the diagnosis of most dementias. The combination of dementia with cerebellar signs or myoclonus can raise the suspicion of CJD. Akinetic mutism and periodic sharp wave complexes on EEG appear to be more specific for CJD. CSF analysis can provide sensitive and specific markers for the disease. In a prospective study of 250 patients with possible CJD, the CSF determinations of the 14-3-3 and tau proteins were proven valuable tools in CJD diagnosis.23 Sensitivities for the 14-3-3 and tau proteins in CSF were 100% and 87% respectively and specificities were 93% and 98% respectively. Detection of CSF tau protein had the highest positive predictive value while detection of CSF 14-3-3 protein had the highest negative predictive value.23 Although every effort should be undertaken to avoid biopsy of a patient with possible CJD disease, atypical presentation or imaging features, on rare occasions, may require a diagnostic biopsy. The neurosurgeon is likely to be called for an opinion or to confirm the diagnosis, pref-
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erably by an open block biopsy. Special precautions when handling the neurosurgical instruments and biopsy material are necessary. Information for UK guidelines can be found at the UK Department of Health website.24 Infection Control Guidelines for transmissible spongiform encephalopathies were published in 1999 and can be found at the WHO website.25 Prions, the transmissible particles that are devoid of nucleic acid and are composed of a modified protein (PrPSc) can cause not only infectious but also genetic and sporadic disorders. Fatal spongiform encephalopathies including bovine spongiform encephalopathy, scrapie of sheep and CJD are notable prion diseases. The key mechanism is the transition of the normal cellular PrP (PrPC) to the abnormal PrPSc through a post-translational process during which the PrPC acquires the high b-sheet content.26 The main differential diagnosis in dementias sufficiently unusual to require a brain biopsy, is an atypical presentation of AD. The amyloid observed in amyloid angiopathy is often identical to the b-amyloid observed in AD although most patients with CAA do not have AD. A population based study suggested that individuals with both CAA and AD had substantially worse cognitive performance during life compared with patients with AD alone, supporting the possibility of a synergistic relationship of the two entities.27,28
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In addition, AD is characterized by intracellular fibril deposition. Kidd described intracellular paired helical filaments that displayed green polarization after staining with Congo red.29 These fibrils consist mainly of the microtubule-associated protein tau, and are most commonly seen in AD although they are not specific for the disease. They are 12 to 12.5 nm wide and have a helical periodic twist of 80 nm.5 In the spongiform encephalopathies of Kuru and CJD, microtubules with a diameter of 10 to 13 nm and transverse periodicity may be demonstrated.5,30 Current research efforts aim toward understanding the folding pathways of the prion proteins since it appears that the propagation of spongiform encephalopathies requires the conversion of the PrPC to the misfolded oligomeric form, PrPSc.31 1.3.4. Amyloid and the spine: Original illustrative case A 75-year-old woman presented with a 16 year history of progressive lower limb stiffness. Neurological examination showed markedly increased tone in her lower limbs with brisk reflexes. MRI of her cervical spine showed extensive pannus formation with a cystic lesion resembling a toadstool causing anterolateral compression of the medulla and the upper cervical cord (Figs. 5A–B). A mild erosion of the posterior cortical margin of C2 was also present but there was no instability on flexion/extension films.
Fig. 5. Spinal amyloidosis. (A) Sagittal T2-Weighted MRI demonstrates a high signal lesion anterior to the lower medulla and higher spinal cord. (B) Axial view through the lesion shows an extra-axial lesion compressing antero-laterally the upper cervical cord. The biopsy tissue consists of fibrocartilaginous material with diffuse and globular amyloid deposits (C, H&E), (D, Congo red brightfield), (E, Congo red polarised light) (original magnifications ·200).
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She underwent a C1/C2 laminectomy with excision of the cystic mass. Pathological examination showed degenerative ligamentous tissue with considerable deposition of amyloid confirmed by Congo red stain. (Figs. 5C–E) Routine laboratory investigations, bone marrow scan, SAP scan and cardiac echo were normal. There was no evidence of systemic amyloidosis. Immunohistochemistry studies excluded AA and ATTR amyloidosis but not the immunoglobulin light chain form of the disease. Although immunostaining with light chain antisera was negative this was still consistent with AL amyloidosis as in this form only half the cases are stainable with commercial antisera. Spinal amyloidomas have been described in the literature and are usually confined to the extradural space with or without bony involvement.14,32 The thoracic and cervical spine are most commonly involved. The extradural amyloid mass produces symptoms or deficits according to its location and most commonly spans one or two vertebral levels. Axial pain, paraparesis and sensory level predominate in the usually acute clinical presentation. Bony involvement including not only the arch but also the vertebral body has been described. The slow growing lesion may involve soft tissues and appear calcified.32,33 The differential diagnosis includes primary or metastatic bone tumour, plasmocytoma or granulomatous lesions.14 Imaging features demonstrate hypo- or iso-intensity in both T1-weighted images and iso- or hyper-intensity in T2-weighted MRI.32,34,35 Histological examination of human intervertebral discs taken from autopsies as well as from surgical procedures demonstrated the presence of lipofuscin and amyloid deposition.36 Although the clinical significance of this observation is not determined at present, it is obvious that the presence of amyloid is a sign of ageing in the intervertebral disc as well as in other tissues. Surgical excision of spinal amyloid collections may release the mass effect exerted upon the spinal cord or nerve roots, control the axial or limb pain, and improve neurological deficits.14,32 2. Conclusions The neurosurgeon and neurologist will encounter in his/ her practice diseases of the brain and spine caused by amyloid deposits. Spontaneous lobar haemorrhages in the elderly are common examples but the tumour-mimicking intracerebral and spinal amyloidomas may also present and should be borne in mind as early diagnosis might significantly affect management and prognosis. References 1. Glenner GC. Amyloid deposits and amyloidosis. Part I. N Engl J Med 1980;302:1283–92. 2. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349:583–96. 3. Selkoe DJ. Folding proteins in fatal ways. Nature 2003;426:900–4.
4. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898–909. 5. Glenner GC. Amyloid deposits and amyloidosis. Part II. N Engl J Med 1980;302:1333–43. 6. Revesz T, Ghiso J, Lashley T, et al. Cerebral amyloid angiopathies: A pathologic, biochemical, and genetic view. Journal of Neuropathology and Experimental Neurology 2003;62:885–98. 7. Yamaguchi H, Yamazaki T, Lemere CA, Frosch MP, Selkoe DJ. Beta amyloid is focally deposited within the outer membrane in the amyloid angiopathy of Alzheimer’s disease: an immunoelectron microscopic study. Am J Pathol 1992;141:249–59. 8. Passero S, Burgalassi L, D’Andrea P, Batisstini N. Recurrence of bleeding in patients with primary intracerebral haemorrhage. Stroke 1995;26:1189–92. 9. Nean JP, Ingrand P, Conderq C, et al. Recurrent intracerebral haemorrhage. Neurology 1997;49:106–13. 10. Qureshi AI, Tuhrim S, Broderick JP, Butjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–60. 11. O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral haemorrhage. N Engl J Med 2000;342:240–5. 12. Wagle WA, Smith TW, Weiner M. Intracerebral haemorrhage caused by cerebral amyloid angiopathy: radiographic-pathologic correlation. AJNR Am J Neuroradiol 1984;5:171–6. 13. Case records of the Massachusetts General Hospital. Case 22-1996. N Engl J Med 1996; 335:189–196. 14. Suri VS, Tatke M, Kumar S, Gupta V. Amyloidoma of the thoracic spine. J Neurosurg (Spine) 2001;94:299–301. 15. Kuratsu J, Matsukado Y, Miura M. Prolactinoma of pituitary with associated amyloid-like substances. Case report. J Neurosurg 1983;59:1067–70. 16. Mori H, Mori S, Saitoh Y, et al. Growth-hormone producing pituitary adenoma with crystal-like amyloid immunochemically positive for growth hormone. Cancer 1985;55:96–102. 17. Matsumoto T, Tani E, Maeda Y, et al. Amyloidomas in the cerebellopontine angle and jugular foramen. Case Report. J Neurosurg 1985;62:592–6. 18. O’Brien TJ, McKelvie PA, Vrodos N. Bilateral trigeminal amyloidoma: an unusual case of trigeminal neuropathy with review of the literature. J Neurosurg 1994;81:780–3. 19. Saltykow S. Zur Frage des lokalen Amyloids der Hirngefasse. Bemerkung zu dem Aufsatz von Morgenstern. Virchows Arch (Pathol Anat) 1935;295:590. 20. Gandhi D, Wee R, Goyal M. CT and MR imaging of intracerebral amyloidoma: Case report and review of the Literature. AJNR Am J Neuroradiol 2003;24:519–22. 21. Spaar FW, Goebel HH, Volles E, Wickboldt J. Tumor-like amyloid formation (amyloidoma) in the brain. J Neurol 1981;224:171–82. 22. Townsend JJ, Tomiyasu U, MacKay A, Wilson CB. Central nervous system amyloidosis presenting as a mass lesion. Report of two cases. J Neurosurg 1982;56:439–42. 23. Everbroeck BV, Quoilin S, Boons J, Martin JJ, Cras PP. A prospective study of CSF markers in 250 patients with possible Creutzfeldt–Jakob disease. J Neurol Neurosurg Psychiatry 2003;74: 1210–4. 24. http://www.dh.gov.uk/assetRoot/04/08/27/21/04082721.PDF. 25. http://www.who.int/emc-documents/tse/whocdscsraph2003c.html. 26. Prusiner SB. Prions. Proc Natl Acad Sci USA 1998;95:13363–83. 27. Greenberg SM. Cerebral amyloid angiopathy and dementia. Neurology 2002;58:1578–88. 28. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 2002;58:1629–34. 29. Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 1963;197:192–3. 30. Chou SM, Martin JD. Kuru plaques in a case of Creutzfeldt-Jacob disease. Acta Neuropathol (Berl) 1971;17:150–5.
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34. Dickman CA, Sonntag VK, Johnson P, Medina M. Amyloidoma of the cervical spine: a case report. Neurosurgery 1988;22:419–22. 35. Meyers SP, Mullins KJ, Kazee AM. Unifocal primary amyloidoma of the spine causing compression of the cervical spinal cord: MR findings. J Comput Assist Tomogr 1996;20:592–3. 36. Yasuma T, Arai K, Suzuki F. Age-related phenomena in the lumbar intervertebral discs. Lipofuscin and amyloid deposition. Spine 1992;17: 1194–8.