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MYELOPATHIES IN HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION

A clinical and pathological study with particular reference to the pathogenesis of vacuolar myelopathy

Dr Stella Veronica Tan Su-Ming

Department of Clinical Neurosciences, Charing Cross & Westminster Medical School

and

Department of Neuropathology, Institute of Neurology

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ProQuest Number: 10105648

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ABSTRACT

The clinical and pathological features of 51 patients with myelopathy (one of whom had two presentations) drawn from a population of approximately 1900 HIV-seropositive patients were studied over 26 months. Vacuolar myelopathy (VM)(n=26, 50%)

commonly presented subacutely. Chnical variants included pure spastic paraparesis and no sustained weakness throughout follow-up. Cognitive dysfunction, cerebral atrophy and peripheral neuropathy were common. Most progressed to wheelchair dependence and bladder incontinence.

Other myelopathies (OTM)(n=26) divided into (i) those with immunosuppression as a predisposing factor (CMV, Herpes zoster, lymphoma), and (ii) those with myelopathy incidental to HIV disease (cervical spondylosis, cord contusion, etc.). CMV was the commonest cause.

Post mortems in 10 VM and 4 OTM confirmed the clinical diagnosis in all.

The annual incidence of all myelopathies was 1.1% in all HlV-seropositives, 3.5% in AIDS, 0.6% in symptomatic non-AIDS, and 0.1% in well séropositives. The incidence of vacuolar myelopathy was 0.6% of all HlV-seropositives, 2% in AIDS and 0.2% in symptomatic non-AIDS patients.

HIV and nutritional parameters, serum B12 and folate were not different in VM, OTM, or sequential admission (n=51) and neurologically asymptomatic (n=30) controls.

Survival analysis of patients with myelopathy showed no significant difference with 49 AIDS controls.

A pathogenetic role for TNFa in VM was investigated by immunocytochemistry. The amount of staining in macrophages, microgha and endothelial cells was higher in 15 cords with VM than in 9 HIV-seropositive and HIV-seronegative controls. Its distribution corresponded to the areas of pathology. CSF and blood TNFce levels (ELISA) were no higher in 16 VM, than in 8 OTM and 47 HIV-seropositive and seronegative controls.

A morphometric study of 20 cords with VM suggested a rostral progression in disease and early macrophage involvement in the pathogenesis of VM.

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ACKNOWLEDGMENTS

I am most grateful for the warm support, encouragement, and advice of my supervisors Dr RJ Guiloff, Consultant Neurologist, of the Academic Department of Clinical

Neurosciences, Charing Cross and Hammersmith Hospitals Trust, and Professor F

Scaravilli, Consultant Neuropathologist, of the Department of Neuropathology, Institute of Neurology.

This work has been facilitated by the collaboration, cooperation and support of many physicians, scientists and laboratory staff to whom I am most grateful, in particular. Dr BG Gazzard of the Department of Medicine, Chelsea and Westminster Hospitals; Dr DC Henderson, Dr A Rowbottom and Dr P Riches of the Department of Immunology,

Chelsea and Westminster Hospitals; Dr A Ciardi and Mr A Beckett of the Department of Neuropathology, Institute of Neurology; Dr JN Harcourt-Webster of the Department of Pathology, Westminster Hospital; Dr R Surtees of the Department of Neurology, Institute of Child Health, Dr S Lucas of the Department of Pathology, the Middlesex Hospital; Dr M Sherratt of the Department of Neurophysiology, Chelsea and Westminster Hospitals; Dr G Tatler, of the Department of Radiology, Westminster Hospital and the National Hospital for Neurology and Neurosurgery; Dr R Colquhoun, of the Department of Neuroradiology, Charing Cross and Hammersmith Hospitals Trust; Dr C Costello of the Department of Haematology, Chelsea and Westminster Hospitals; and Dr RD Hoare and Miss Christina Robertson of the Department of Neuroradiology, the Churchill Clinic. In addition, I am grateful to Professor MJG Harrison, of the Department of Neurology, and Dr R Miller, of the Department of Respiratory Medicine, the Middlesex Hospital for permission to study patients under their care; and to Prof GE Griffin, and Dr R Shattock of the Department of Infectious Diseases, St Georges’s Hospital, for the use of their P3 containment Laboratory.

I am indebted to the patients and their next of kin, who willingly participated in the study and kindly permitted the study of post mortem material.

I would also like to thank Mr M Nelson and the staff of the photographic department at the Charing Cross and Chelsea and Westminster Hospitals for their help in the processing of the photomicrographs and in producing the digital prints, and Miss J Roberts for her kind help with the typing of references.

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CONTENTS Page

ABSTRACT 2

ACKNOWLEDGMENTS 3

TABLE OF CONTENTS 4

LIST OF TABLES 5

LIST OF FIGURES 7

GLOSSARY OF ABBREVIATIONS 10

SECTION I. INTRODUCTION Chapter

1. Introduction 13

2. Literature review 16

3. Questions and approach 56

SECTION II. HIV ASSOCIATED MYELOPATHIES: CLINICAL FEATURES AND NATURAL HISTORY

4. Clinical methods 60

5. Laboratory and imaging techniques 68

6. Pathology methods 75

7. Statistics 79

8. Patient and control populations 81

9. Vacuolar myelopathy - clinical features 89

10. Other myelopathies - clinical features 120

11. Incidence, clinical associations and survival 152

12. Pathology 184

SECTION III. VACUOLAR MYELOPATHY: PATHOLOGY AND PATHOGENESIS

PART L TNFa AND VACUOLAR MYELOPATHY

13. Introduction 204

14. Materials and methods 205

15. Results 210

16. Discussion and Summary 219

PART2. MORPHOLOGY AND MORPHOMETRY

17. Introduction 221

18. Materials and methods 222

19. Results 233

20. Discussion and Summary 248

PART 3. HYPOTHESIS

21. Hypothesis on the pathogenesis of vacuolar myelopathy, 251

dementia and peripheral neuropathy

SECTION IV. CONCLUSIONS

22. Summary and further studies 265

APPENDIX 1: Tables 271

APPENDIX 2: Case Histories 279

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LIST OF TABLES

Chapter 2

2.1 Literature review. Vacuolar myelopathy - Clinical features. 2.2 Literature review. Vacuolar myelopathy - Investigations and

pathology

Page

45 50

Chapter 5

5.1 Protocols for CT scans of the head and spine.

5.2 Standard settings for MRI scans of the brain and spine.

73 74

Chapter 8

8.1 Sequential admissions. Neurological symptoms and signs. 8.2 Sequential admissions. HIV and nutritional parameters. 8.3 Sequential admissions. HIV-related diseases.

8.4 Neurologically asymptomatic patients. HIV and nutritional parameters.

Chapter 9

9.2.1 Clinically definite VM. HIV and nutritional parameters.

9.2.2 Clinically definite VM. HIV-related diseases at presentation of myelopathy.

9.2.3 Clinically definite VM. Cerebrospinal fluid examination results. 9.2.4 Clinically definite VM. Brain and spinal cord imaging.

9.3.1 Suspected VM. HIV and nutritional parameters.

9.3.2 Suspected VM. HIV-related diseases at presentation of myelopathy. 9.3.3 Suspected VM. Cerebrospinal fluid examination results.

9.3.4 Suspected VM. Brain and spinal cord imaging.

85 86 87 88 111 112 113 114 115 116 117 118

Chapter 10

10.1 Other myelopathies. HIV and nutritional parameters. 146

10.2 Other myelopathies. HIV-related diseases at presentation of myelopathy. 147 10.3 Other myelopathies. Cerebrospinal fluid examination results. 148

10.4 Other myelopathies. Brain and spinal cord imaging. 149

Chapter 11

11.3.1 Comparisons of HIV and nutritional parameters. Myelopathy patients and 156 controls.

11.4.1 Concurrent HIV-related diseases. Myelopathy patients and sequential 162 admission controls.

11.4.2 Total HIV-related diseases. Myelopathy patients and sequential admission 162 controls.

11.4.3 Total HIV-related diseases. "Pure" myelopathy and myeloradiculopathies. 162 11.4.4 AIDS indicator diseases and main diagnoses at death. Vacuolar 163

myelopathy.

11.4.5 AIDS indicator diseases and main diagnoses at death. Other myelopathies. 164

11.4.6 AIDS indicator diseases. Sequential admissions. 165

11.5.1 CT scan controls. Chnical features and CT scan results of sixty male HIV 173 -seropositive patients.

11.5.2 Mini-Mental Scores. Myelopathy patients and controls. 174 11.5.3 Mini-Mental Scores and corresponding lower limb disability scores in 175

patients with VM and OTM.

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Page

11.6.2 Survival data. Other myelopathies. 180

11.6.3 Survival data. Sequential admissions. 181

Chapter 12

12.1 Chnical features at presentation and final follow-up, and spinal cord 197 pathology in patients with clinicaUy definite and suspected VM.

12.2 Associated clinical features and pathology outside the spinal cord in 198 patients with chnically definite and suspected VM.

12.3 Post mortem findings in patients with OTM 199

Chapter 15

15.1 TNFof immunostaining in spinal cords of patients with vacuolar 213 myelopathy.

15.2 TNFa immunostaining in spinal cords of HIV seropositive patients 214 without VM.

15.3 TNFa Immunostaining in spinal cords of HIV seronegative controls. 214 15.4 CSF and Blood levels of TNFa in patients with Vacuolar myelopathy 215

and HIV seropositive and HIV seronegative controls.

Chapter 19

19.1 Clinical and pathological features of 20 patients with vacuolar 238 myelopathy.

19.2 Anterior column raw sub scores for myelin change, vacuolation and 239 macrophage density at different cord levels in 20 AIDS patients with

vacuolar myelopathy.

19.3 Lateral column raw sub scores for myelin change, vacuolation and 240 macrophage density at different cord levels in 20 AIDS patients with

vacuolar myelopathy.

19.4 Posterior column raw subscores for myelin change, vacuolation and 241 macrophage density at different cord levels in 20 AIDS patients with

vacuolar myelopathy.

19.5 Column and cord scores in 20 patients with VM. 242

19.6 Cord Level severity scores in vacuolar myelopathy (see methods). 244 19.7 Median and (interquartile ranges) of Column Level scores in the anterior, 245

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L IS T OF FIGURES Legends to Figures

Page

Chapter 9

Figure 9.1 Vacuolar myelopathy. Normal MRI of the spinal cord (T1 119 weighted image)(case 20).

Figure 9.2 MRI of the brain showing cerebral atrophy (T1 weighted image) 119 (case 26).

Chapter 10

Figure 10.1 MRI of the lower spinal cord (a) before and (b) after injection 150 of gadohnium, showing enhancement of the anterior surface of the conus and lumbosacral cord (T1 weighted images). CMV myelitis (case 30).

Figure 10.2 MRI of the lower spinal cord post gadolinium showing enhancing 151 lymphomatous lesions in the L2 and L5 vertebrae (case 35) (T1

weighted image).

Figure 10.3 MRI of the cervical cord; (a) sagittal image (T2 weighted) and 151 (b) axial image (T1 weighted) showing cord compression at C5/6, worse on the right (case 49).

Chapter 11

Figure 11.6.1 Survival after AIDS diagnosis. All myelopathies v sequential 182 admissions.

Figure 11.6.2 Survival after AIDS diagnosis. VM v sequential admissions. 182

Figure 11.6.3 Survival after AIDS diagnosis. VM v other myelopathies. 182

Figure 11.6.4 Survival after onset of myelopathy. VM v other myelopathies. 183

Chapter 12

Figure 12.1 Vacuolar myelopathy. Thoracic cord showing (a) myelin pallor 200 (case 2) (Luxol fast blue/Cresyl violet x 10), and (b) macrophages within vacuoles (case 7) (Ricinus communis agglutinin x 100).

Figure 12.2 HIV myelitis (case 20). Multinucleated giant cells in the thoracic 201 cord. (Haematoxyhn and eosin x 100).

Figure 12.3 Herpes zoster myelitis (case 32). Thoracic cord showing 201 immunostaining (red) for HZV antigen (xlOO).

Figure 12.4 Lymphomatous myeloradiculitis (case 35). Sacral cord showing 201 subpial infiltration by lymphoma cells (Haematoxyhn and

eosin x 40).

Figure 12.5 CMV myeloradiculitis (case 40). Conus showing (a) macrophages 202 (Ricinus communis agglutinin x 10) (b) CMV DNA on in situ

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Chapter 15

Figure 15.1

Figure 15.2

Figure 15.3

Chapter 18

Figure 18.1

Grades of TNFa immunostaining (blue) in the cytoplasm (see methods). Nuclei are counterstained with nuclear fast red. Most cells shown are macrophages or microgha. a. very mild (+-) (case 158); b. mild (+ ) (case 157); c. moderate ( + + ) (case 100); d. severe (+ + + ) (case 2); and e. negative control, (x 160, original magnification).

Grades of TNFa immunostaining (as in figure 2) shown at lower power, a. mild (+)(case 157) (x 100, original magnification); b. moderate (++)(case 100); c. severe (+ + +)(case 2). (x 40, original magnification)

Morphology of cell types staining for TNFa. a. "foamy" macrophage (arrow); b. microglial cell (arrow); c. endothelial cells (lining blood vessels, arrow). (xl60, original magnification).

Tracing of projected mid-thoracic cord (case 14) stained with Luxol Fast Blue/cresyl violet showing the areas and corresponding grades for myelin pallor. The dotted lines indicate the lateral limit of the anterior columns as defined in the methods.

Page

216

217

218

229

Figure 18.2

Figure 18.3

Figure 18.4

Chapter 19

Figure 19.1

Figure 19.2

Grades for myelin change (a) grade 1; (b) grade 2; (c) grade 3; 230 (d) grade 4; (e) grade 5. (Luxol Fast Blue/Cresyl violet x 40,

original magnification)

Grades for vacuolation (a) grade 1; (b) grade 2; (c) grade 3; 231 (d) grade 4; (e) grade 5. (Haematoxyhn and eosin x 40, original magnification)

Grades for macrophage density (a) grade 1; (b) grade 2; (c) 232 grade 3; (d) grade 4; (e) grade 5. (Ricinus communis agglutinin

X 40, original magnification)

Photomicrographs of the lateral columns of the spinal cord of 246 patients with mild (a,b, case 168), moderate (c,d, case 8), and

severe (e,f, case 2) VM, showing the prominence of activated

microgha (arrowheads) and macrophages (arrows)(RCA, left column) compared to the less obvious degree of vacuolation (H&E, right column) in mild and moderate VM. Both features are equally prominent in severe VM. (H&E x 60 a,c,e; RCA x 60 b,d,f).

Photomicrographs of cervical (a,c) and mid-thoracic (b,d) sections of the spinal cord in severe (a,b, case 18) and moderate (c,d, case 101) VM, showing the localisation of pathological change at thoracic level in moderate VM, and the equally severe pathological changes at cervical and thoracic levels in severe VM (Luxol Fast Blue/Cresyl Violet x 10).

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Page

Chapter 21

Figure 21.1 Hypothesis on the pathogenesis of Vacuolar myelopathy, 262 Dementia, Cerebral atrophy and Peripheral neuropathy in HIV

disease. A schematic representation.

Figure 21.2 The single carbon (methyl) transfer pathway. Relationship 263 with B12 and glutathione metabohsm. (Modified from Surtees

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GLOSSARY OF ABBREVIATIONS

AC anterior columns of the spinal cord

AIDS acquired immunodeficiency syndrome

BMI body mass index

BSAEP brain stem auditory evoked potentials

CFT complement fixation test

Ch chapter

CMV cytomegalovirus

CMYK cytomegalovirus encephalitis

CNS central nervous system

cs case or cases

CSF cerebrospinal fluid

CT computerised axial tomography

DDI didanosine

DEAFF detection of early antigen fluorescent foci

Dem dementia

DEP dermatomal evoked potentials

DRG dorsal root ganglion

EIA enzyme immuno assay

ELISA enzyme-linked immunosorbant assay

EMG electromyography

EPs evoked potentials

ETA Fluorescent treponemal antigen

GFAP glial fibrillary acidic protein

GM-CSF granulocyte-monocyte colony stimulating factor

GSH glutathione

GT Dr George Tatler

H&E haemagglutinin and eosin

HIV human immunodeficiency virus (refers to HIV-1 unless stated otherwise)

HIVE human immunodeficiency virus encephalitis

HlVlep human immunodeficiency virus leukoencephalitis

HIV p24 human immunodeficiency virus p24 core antigen

HLA human leucocyte antigen

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HTLV-1 human T-cell leukaemia virus-1

HZV herpes zoster virus

IF immunofluorescence

IFN interferon

IL interleukin

KS Kaposi’s sarcoma

LC lateral columns of the spinal cord

LFB luxol-fast blue

LL lower limbs

LMN lower motor neurone

MAI mycobacterium avium-intracellulare

MGC multinucleated giant cell

MGN microglial nodule

MMS mini-mental score

MND motor neurone disease

MRC Medical Research Council

MRI magnetic resonance imaging

NA neurologically asymptomatic HIV-seropositive controls

NCS nerve conduction studies

NN nodules of Nageotte

NO nitric oxide

NOS nitric oxide synthase

OTM other myelopathies

PC posterior columns of the spinal cord

PGP pneumocystis carinii pneumonia

PGR polymerase chain reaction

PM post mortem

PN peripheral neuropathy

RGA Ricinus communis agglutinin

RJG Dr Roberto Jaime Guiloff

SA sequential admission HIV-seropositive controls

SACD subacute combined degeneration of the cord

SAH S-adenosylhomocysteine

SAM S-adenosylmethionine

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SNA symptomatic non-AIDS HlV-seropositives

SVT Dr Stella Veronica Tan (Su-Ming)

TNFa: tumor necrosis factor-alpha

TPHA Treponema pallidum haemagglutination assay

UL upper limbs

UMN upper motor neurone

VDRL Venereal Disease Research Laboratory (assay)

VEP visual evoked responses

VM vacuolar myelopathy

VMD clinically definite vacuolar myelopathy

VMS suspected vacuolar myelopathy

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13

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CHAPTER 1. INTRODUCTION

As a child, I was introduced to the world of microbes by my mother, a virologist, who stocked our home hbrary with beautifully illustrated books of man’s early triumphs over a host of microscopic creatures. As BSc student, I learnt to respect viruses in particular, particles which seemed so effortlessly to usurp and exploit the body’s defense

mechanisms. It was late that year that I first heard of the emergence of a new epidemic, not yet established in Britain, but almost certainly at our doorstep. It was my introduction to HIV and AIDS.

It was soon apparent that nervous system disease was common and a major cause of morbidity and mortality in patients with AIDS. Spinal cord disease, although commonly reported pathologically, was poorly documented clinically. In particular, the aetiology of the most common, vacuolar myelopathy, was unknown. In this study, I set out to

document the incidence, clinical spectrum and natural history of the myelopathies seen in this population, and to investigate some of the possible mechanisms which may be involved in the pathogenesis of vacuolar myelopathy. The following outlines the organisation of this thesis:

The reader will be helped by a short abstract which is followed by the table of contents, lists of tables and figures and a summary of the abbreviations used.

Section I contains the introductory chapters, providing a brief outline of the beginnings of the clinical pandemic, the discovery, origins and nature of the virus and its associated manifestations within the nervous system, followed by a historical review of the

myelopathies in HIV infection. I have chosen to review the literature on vacuolar myelopathy until the start of this thesis in August 1991, when the questions were posed and the approach to address them was dehneated, as outlined in chapter 3. Publications up to December 1996 are included in summary tables in the review section, and in the

discussions of results in subsequent chapters. The literature on the other, less enigmatic, myelopathies is reviewed till December 1996.

Section II contains the methods, results, discussions and conclusions on the clinical features and natural history of myelopathies in HIV infection based on a prospective clinicopathological study of 51 patients studied over 26 months. Each chapter starts with a listing of the subheadings within it. The clinical methods are described in chapter 4, the laboratory and imaging techniques in chapter 5, the routine pathological methods in chapter 6, and the statistical methods in chapter 7. Further details on methods and

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15 described in chapter 8. In chapter 9, the clinical features of the clinically definite and clinically suspected vacuolar myelopathy groups are first described separately. Their differences and similarities are subsequently compared and the justification for combining the groups as one discussed. In chapter 10, the other myelopathies seen are described and compared with those in the HIV and non-HIV literature. The incidence and prevalence of the different myelopathies, the HIV and nutritional parameters, infections, other HIV associated diseases, cognitive function, cerebral atrophy and survival in patients with vacuolar myelopathy, other myelopathies and appropriate controls are described and compared in chapter 11. The pathological findings in the fourteen patients with post mortem examinations are described in chapter 12, and the clinical spectrum in the

pathologically confirmed vacuolar myelopathy cases compared with that of the rest of the vacuolar myelopathy group.

Section III contains two studies addressing the question of the pathogenesis of vacuolar myelopathy. In Part 1 (chapters 13-16), the presence of tumor necrosis factor-alpha within the spinal cord is sought by immunocy tochemistry, and tumor necrosis factor-alpha levels assayed in the cerebrospinal fluid and blood using an ELISA technique. The findings in patients with vacuolar myelopathy and HIV-seropositive and HIV-seronegative controls are compared. Part 2 (chapters 17-20) examines the morphological and morphometric aspects of vacuolar myelopathy to determine whether (i) there is evidence that macrophage activation precedes the formation of vacuoles and myelin pallor and, therefore, may be aetiologically associated with their pathogenesis, and (ii) there is evidence of significant Wallerian degeneration or a dying back phenomenon. A hypothesis on the pathogenesis of vacuolar myelopathy follows in Part 3 (chapter 21).

The final chapter, in Section IV, summarises the findings of this thesis and suggests further studies and therapeutic manoeuvres.

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16 CHAPTER 2. LITERATURE REVIEW

2.1 The Beginnings of the Pandemic

2.2 Virological Aspects 2.2.1 Isolation 2.2.2 Origins 2.2.3 Structure 2.2.4 The Genome

2.2.5 The replication cycle

2.2.5.1 Attachment and entry

2.2.5.2 Reverse transcription and integration 2.2.5.3 Viral latency

2.2.5.4 Transcription, assembly and release 2.2.6 Outcome of cellular infection

2.3 Clinical stages and the CDC classification of AIDS 2.3.1 Natural history

2.3.1.1 Seroconversion

2.3.1.2 Asymptomatic infection and persistent generalized lymphadenopathy

2.3.1.3 Symptomatic non-AIDS (including ARC) and AIDS 2.3.2 Classification of HIV infection

2.4 Neurological disease in HIV-infection

2.4.1 Neurological complications in early HIV infection 2.4.2 Neurological complications in late HIV infection

2.4.2.1 Immune deficiency related 2.4.2.2 Direct effects of HIV 2.4.2.3 Uncertain mechanisms

2.5 Myelopathies in HIV-1 infection

2.5.1 Vacuolar Myelopathy (review up to August 1991) 2.5.1.1 Clinical aspects

2.5.1.2 Pathology and unresolved pathological issues 2.5.1.3 Theories on pathogenesis

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CHAPTER 2 LITERATURE REVIEW

2.1 THE BEGINNINGS OF THE PANDEMIC

The first clinical cases of HIV-1 related acquired immunodeficiency syndrome in the literature were probably in an ex-sailor and his family in Norway in the 1960s (Froland et al 1988). However, it was not until 1981, when a high incidence of Kaposi’s sarcoma, and the Pneumocystis carinii pneumonia were reported in previously healthy homosexual men in New York and California (CDC 1981a, CDC 1981b, Gottlieb 1981), that the emergence of "acquired immunodeficiency syndrome" (AIDS) as a new disease was recognised.

Although the initial epidemiological evidence strongly suggested a sexual means of transmission, there was soon evidence of blood borne infection, as cases of AIDS began to be reported in patients with haemophilia A (CDC 1982a), recipients of blood

transfusions (CDC 1982b, Amman et al 1983), children of women at high risk of AIDS (CDC 1982c), and intravenous drug users (Wormser et al 1983). In a third group, Haitian immigrants (CDC 1982d), heterosexual contact was later found to be the main mode of transmission (Pape et al 1985, Johnson et al 1985, The Collaborative Study Group of AIDS in Haitian-Americans 1987).

Despite the initial focus of infection in the homosexual population, it is heterosexual transmission that has emerged as the greatest threat to worldwide communities. The co­ presence of genital ulcer disease appears to be a facilitating factor (Plummer et al 1991). AIDS is also transmitted vertically from mother to child in utero (Blanche et al 1989, European Collaborative Study 1988, Sprecher et al 1986), and postnatally in breast milk (Oxtoby 1988, Thiry et al 1985).

Currently the epidemic appears to have stabilised in the developed countries, but continues to expand relentlessly in economically deprived countries, in which 85% of the worldwide population of an estimated 17 million HIV-infected individuals and four million AIDS cases reside (WHO 1994). The next decade is likely to see a continued escalation of the disease particularly in Africa, South East Asia and India.

2.2 VIROLOGICAL ASPECTS

2.2.1 Isolation. HIV-1 was isolated from a lymph-node of a patient at risk of AIDS in 1983 (Barré-Sinoussi et al 1983). HIV-2 was first isolated in 1986 in West African patients with an AIDS-like condition (Clavel et al 1986a). It has since been shown to cause AIDS (Brun-Vezinet et al 1987, CDC 1988), but is endemic only in West Africa (Pinto et al 1991).

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18 was from a person in Kinshasa, Zaire in 1959 (Nahmias et al 1986), and the earliest documented case with AIDS was known to have visited African ports (Froland 1988), suggesting that the original focus of HIV-1 infection was probably in Central Africa.

HIV-1 is genetically closely related to an isolate of SIV from a chimpanzee in Gabon (Huet et al 1990). HIV-2 is closely related to a simian immunodeficiency virus (SIV) from sooty mangabeys (Dietrich et al 1989, Marx et al 1991). It is likely that both the HIV-1 and HIV-2 epidemics are the result of simian/human cross-species transmissions (Myers et al 1992). Genomic studies suggest that the HIV viruses may have arisen from a common primate progenitor as recently as 40-50 years ago (Smith et al 1988b).

2.2.3 Structure. The HIV viruses belong to the lentivirinae subfamily of the Retroviridae

family (Greene 1991). Retroviruses have in common a similar virion structure, genomic organization and replication cycle in which their RNA genomes are replicated via a DNA intermediate (Shaunak and Weber 1992). Lentiviral infections are notable for their long periods of clinical latency followed by a protracted symptomatic phase, a weak humoral immune response complicated by persistent viraemia, and involvement of the nervous system (Letvin 1988).

The two HIV viruses are similar except for certain sequences of their genomes which largely manifest as differences in antigenic components in the envelope glycoproteins (Clavel et al 1986b). Only HIV-1 will be described here.

On electron microcopy, the HIV-1 virion is an icosahedral structure containing 72 external "spikes" formed by the two major viral-envelope proteins, gpl20 and gp41. The viral lipid envelope, acquired from the host cell during viral budding, also contains various host proteins, including the Class I and II major histocompatibility antigens. The viral core contains 2 copies of the HIV-1 9-kilobase single stranded genomic RNA, associated with preformed viral enzymes. The core also contains 4 nucleocapsid proteins, p24, pl7, p9 and p7 (Greene 1991).

2.2.4 The Genome. The HIV-1 genome encodes three structural genes gag, pol, and env,

and at least six regulatory genes (vif, vpu, vpr, tat, rev, and nej). Due to their genetic complexity, both HIV viruses can alter structure, function and immunogenicity of major viral gene products to cause variations in viral virulence and cellular tropism (Fenyo et al

1989). Variations in the viral envelope gene have been shown to determine the ability of some HIV-1 strains to efficiently infect mononuclear phagocytes (Cheng-Mayer et al 1990a, O’Brien et al 1990) and microglia, the predominant cellular lineages infected in the nervous system. Even in a single individual, HIV is present as a "quasispecies" -

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19 1988, Martins et al 1992).

2.2.5 The replication cycle

2.2.5.1 Attachment and entry The first retroviral receptor discovered was the CD4 antigen (Dalgleish et al 1984, Klatzmann et al 1984) which is expressed predominantly on helper T lymphocytes, and less frequently on monocytes, macrophages, and B-

lymphocytes, where it functions as a coreceptor for the T-cell antigen complex (Robey and Axel 1990). Two co-receptors have recently been identified; fusin, required for infection with virus adapted for growth in transformed T-cells lines (Feng et al 1996), and CC-CKR-5, which is the principal cofactor for entry mediated by the envelope

glycoproteins of primary macrophage-tropic stains (Dragic et al 1996, Deng et al 1996). CC-CKR-5 is a receptor for the h-chemokines macrophage inhibitory protein (M lP)-la, MIP-IB, and RANTES (regulated-upon-activation, normal T expressed and secreted), which are capable of blocking entry of non-syncytium forming HIV-1 isolates (Cocchi et al 1995). In vitro studies with glial cells and neurones suggest that galactosyl ceramide (GalC) may be the main cell surface receptor here (Harouse et al 1991a, Bhat et al 1991). However, convincing evidence that productive infection of these cells occurs in vivo is lacking (Sharer 1992).

2.2.5.2 Reverse transcription and integration After internalization and uncoating, a double-stranded DNA replica of the viral genome (provirus) is generated by reverse transcriptase and inserted into the host genome by integrase (Greene 1991) where it remains for the lifetime of the cell.

2.2.5.3 Viral "latency" HIV-1 replicates continuously throughout all stages of infection, and despite the presence of a clinical latency during which there is little or no detectable virus in plasma (Schnittman et al 1989), a true microbiologically-latent state does not occur (Piatak et al 1993, Pantaleo et al 1993a, Embretson et al 1993).

2.2.5.4 Transcription, assembly and release HIV-1 does not replicate in resting T-cells, presumably because critical host factors are absent (Cullen and Greene 1989).

However, activation of these cells by antigens, mitogens, cytokines or transactivator proteins of various viruses (including herpes simplex types 1 and 2, Epstein-Barr virus and cytomegalovirus) can induce high levels of HIV production (Rosenberg and Fauci

1990a, Garcia and Gay nor 1994).

A large number of cytokines capable of inducing HIV-1 gene expression have been identified including tumor necrosis factor-a (TNFa), TNF-6, interleukin (IL)-l, IL-2, IL- 3, IL-4, IL-6, interferon gamma, granulocyte-macrophage and macrophage colony

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20 Gaynor 1994).

Once transcribed, the mRNAs undergo final processing in the cytoplasm, where the viral cores, gag proteins and enzymes are assembled and bud through the plasma membrane as new virion particles.

2.2.6 Outcome of cellular infection

High rates of viral replication in CD4 positive T cells leads to death of the infected cells (Weber 1987). In vitro cell death is preceded by the formation of syncytia between gpl20 expressing infected cells and uninfected CD4 positive cells, which are also killed in the process (Gallo et al 1984). The demise of the cells may be due to interference with normal cellular processing caused by the accumulation of large amounts of unintegrated viral DNA or RNA (Rosenberg and Fauci 1990b). The virus envelope protein gpl20, in itself, may be toxic and has been shown to cause neuronal injury in vitro (Kaiser et al 1990).

Macrophages, however, show little cytopathic effect and little cell killing, and thus form reservoirs of infection. There is some evidence that HIV infection of macrophages can induce increased production of TNFa (Merrill et al 1989) which in turn can up- regulate transcription of integrated HIV (Rosenberg and Fauci 1990b), leading to a positive feedback cycle of TNFa production and HIV replication. The involvement of other cytokines in this cycle may contribute to indirect mechanisms of damage to the CNS by HIV.

2.3 CLINICAL STAGES AND THE CDC CLASSIFICATION OF AIDS 2.3.1 Natural history

The clinical course of HIV infection in man follows a common pattern of development, although the time course of each stage of infection may vary in different individuals (Schrager et al 1994).

2.3.1.1 Seroconversion. Primary infection is followed by a stage of p24 antigenaemia (Lever 1992), during which widespread early dissemination of virus to lymphoid organs (Pantaleo et al 1993a) and the CNS (Ho et al 1985) occurs. This is followed, usually within 1 week-3 months, by the appearance of virus specific IgM and IgG antibodies, and a rapid fall in p24 levels (Pantaleo et al 1993b). In 50-70% a symptomatic seroconversion illness may occur (Tindall and Cooper 1991, Cooper et al 1985, Rustin et al 1986).

2 3 .1 .2 Asymptomatic infection and persistent generalized lymphadenopathy (PGL). A prolonged period of clinical latency of approximately 8-10 years (Bacchetti and Moss

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21 spleen, and extracellular HIV is trapped in follicular dendritic cells (Pantaleo et al 1993a, Embretson et al 1993). In some patients a generalized lymphadenopathy develops. There is a slow progressive decline in the CD4 positive lymphocytes (Pantaleo et al 1993b) despite typically undetectable levels of p24 antigen.

2.3.1.3 Symptomatic non-AIDS (including ARC), and AIDS. As disease progresses, virus trapping and sequestration in lymph nodes fails, and an acceleration of plasma viraemia occurs, with p24 antigen again becoming detectable (Pantaleo et al 1993a). The CD4 cell count falls rapidly, and functional immunodeficiency becomes manifest with constitutional symptoms and signs. Despite treatment, AIDS usually progresses to death within 2 years (Lemp et al 1990).

2.3.2 Classification of HIV infection

Several disease classifications have been devised for staging patients with HIV infection of which the most widely used is that of the Centre for Disease Control, first published in 1986, and revised in 1987 and 1992 (CDC 1986, 1987, 1992).

This system classifies the manifestations of HIV infection into 4 main hierarchical groups (I-IV) (Appendix 1.1). Patients are classified according to the illness that puts them in the highest group. The clinical HIV stages based on the CDC classification are shown in Appendix 1.2.

At the end of 1992, the CDC classification was modified to include, as AIDS

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22 2.4 NEUROLOGICAL DISEASE IN HIV-INFECTION

Neurological disease is common in HIV infection. Snider et al (1983) first documented abnormalities of both the central and peripheral nervous systems in 50 AIDS cases. Levy et al (1985) found neurological symptoms in 39% of patients with AIDS or generalised lymphadenopathy. More recent data suggest over 50% of adult patients and up to 90% of children with AIDS will develop neurological complications (Guiloff et al 1988, Janssen et al 1989). In about 10% of AIDS patients, the neurological complication is the initial manifestation of AIDS (Fuller et al 1989a). In post mortem studies, neurological disease has been reported in up to 80-90% of cases (Anders et al 1986, Navia et al 1986b, Petito et al 1986, Lantos et al 1989).

The neurological complications of HIV disease can be broadly classified into those occurring in the early or late stages of HIV infection. Those in the late stages of HIV infection may be further subdivided as (i) related to immunodeficiency in general (opportunistic infections and tumours), (ii) due to direct effects of HIV infection in the nervous system, and (iii) indirectly related to HIV.

2.4.1 Neurological complications in early HIV infection - Seroconversion related syndromes and aseptic meningitis

Seroconversion may be accompanied by neurological complications including Guillain- Barré syndrome (Piette et al 1986, Vendrall et al 1987), acute symmetrical

polyneuropathy (Hagberg et al 1986), facial nerve palsy (Piette at al 1986, Wiselka et al 1987), bilateral acute brachial neuritis (Calabrese et al 1989), encephalitis (Game et al 1985), and acute myelopathy (Denning et al 1987). The p24 antigen may be detected in the serum (Goudsmit et al 1986a) and, in a proportion of patients, virus is recoverable in the cerebrospinal fluid (CSF) (Ho et al 1985, Piette et al 1986, Hagberg et al 1986, Denning et al 1987). Nevertheless, it is likely that most of these syndromes are mediated by the immunological response to the virus rather than a manifestation of direct viral cytopathogenicity within the nervous system, since similar syndromes may be associated with seroconversion in infections with other agents (Winer et al 1988).

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23

2.4.2 Neurological complications in late HIV infection

2.4.2.1 Immune deficiency related

2.4.2.1.1 Opportunistic infections and tumours. The earliest reports of opportunistic infections included cryptococcal meningitis (Mildvan et al 1982, Snider et al 1983), CMV retinitis (Holland et al 1982), progressive multifocal leukoencephalopathy (PML)(Miller et al 1982, Snider et al 1983), and toxoplasmosis (Snider et al 1983). A more recent clinical study found nervous system opportunistic infections in 21 % of a London clinical series of

122 AIDS patients followed up until death. The most frequent causative agents were CMV, Herpes zoster. Toxoplasma gondii and Cryptococcus neoformans (Guiloff 1989). Tuberculous involvement of the CNS (Bishburg et al 1986) is common in AIDS

worldwide but is uncommon in most European countries. Tuberculous meningitis is similar to that seen in non-AIDS patients, except for the increased incidence of

intracerebral mass lesions (Bishburg et al 1986, Dube et al 1992). Other CNS infections include Herpes simplex (Tan et al 1993), neurosyphilis (Berger 1991), and a large number of infrequent opportunistic infections including amoebae, histoplasmosis, aspergillosis, coccidiodes, nocardia, zygomycosis and listeria meningitis (Guiloff and Tan 1992).

Tumours involving the nervous system include primary and secondary CNS

lymphomas, and more rarely, plasmacytomas and immunoblastic sarcomas (Ziegler et al 1982, Snider et al 1983).

2.4.2.2 Direct effects o f H IV

HIV, in common with other lentiviruses, is neurotropic and capable of causing

neurological disease (Gajdusek et al 1985). There is evidence that the virus enters the CSF soon after primary infection (Ho et al 1985), possibly through infected macrophages, and then persists within the CNS during clinical latency (Goudsmit et al 1986b, Sinclair et al

1994). The only cells within the CNS in which in vivo infection by HIV has been reliably demonstrated are macrophages, microglia and multinucleated giant cells (MGCs) (Sharer et al 1985, Wiley et al 1986, Michaels et al 1988, Meyenhofer et al 1987). The strongest evidence of a direct causal link between the presence of HIV in the brain and

neuropathological change is with HIV encephalitis (Budka et al 1991).

2.4.2.2.1 HIV encephalitis and leukoencephalitis. HIV encephalitis (HIVE) is

characterized pathologically by multiple disseminated foci of microglia, macrophages and multinucleated giant cells. The multinucleated cell represents the hallmark of HIVE (Snider et al 1983, Sharer et al 1985, Budka et al 1986). It consists of two main

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24 compact, central cluster (Sharer et al 1985). Studies with cell markers and

immunocytochemistry have characterized them as macrophage-related cells (Koenig et al 1986), thought by most investigators to have arisen by syncytial formation of infected mononuclear cells, similar to that seen in vitro. In some instances however, MGCs have been shown to have cell processes, suggesting they may have arisen from, or had

incorporated, microglial cells (Dickson 1986, Michaels et al 1988). Other features of HIV encephalitis include loose microglial nodules (Rosenblum 1990, Sharer 1986), and limited white matter pallor. These changes can be found in any part of the CNS, from the

cerebral cortex to the spinal cord, but are most readily identified in the deep white matter of the cerebral hemispheres, the basal ganglia, and the brainstem.

The term HIV leukoencephalopathy (HIVlep) is used where the white matter damage accompanying HIV infection is diffuse and extensive, with myelin loss and reactive astrogliosis but little or no inflammatory infiltrates (Budka et al 1991). It affects the white matter of the cerebral hemisphere usually in symmetric fashion, and may affect the cerebellum. The mechanisms underlying the white matter changes are unclear, and may involve the elaboration of cytokines (Tyor et al 1995).

Clinically, both pathological features have been associated with a progressive dementia with personality and behavioural changes (Glass et al 1993, Tyor et al 1995).

2.4.2.2.2 HFV myelitis. The presence of similar MGCs and foci of inflammation in the spinal cord constitutes HIV myelitis. This will be reviewed in more detail in Ch 2.5. 2.4.2.3 Indirectly related to H IV

Although the presence of HIV has been reported in association with the pathologies described below, indirect mechanisms, possibly exacerbated by the presence of the virus, need to be considered in view of the limited cellular tropism of HIV. There is increasing evidence that many of the neuropathological changes observed in HIV disease are

mediated indirectly by cytokines or factors released by HIV infected macrophages or microglia, or via the viral surface protein gpl20 (see Ch 21).

2.4.2.3.1 Diffuse poliodystrophy. A diffuse poliodystrophy characterized by diffuse reactive astrogliosis and microglial activation of the cerebral grey matter (Budka et al 1987, Budka 1989) is sometimes seen in the cortex, basal ganglia and brain stem nuclei of patients with HIVE, and appears to correlate with the presence of detectable HIV provirus in the brain (Sinclair and Scaravilli 1992). In the absence of convincing evidence of productive viral infection of astrocytes, the astrogliosis is likely to be an indirect effect, possibly via interaction of astrocytes with HIV infected cells or their products.

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25 or multifocal vacuolar myelin swellings and macrophages (similar to that seen in the cord in vacuolar myelopathy, see Ch 2.5) are prominent in cerebral white matter has been described in some patients with dementia (Schmidbauer et al 1990, Budka 1991).

Although the presence of HIV has been demonstrated in some cases, a direct aetiological link has not been established.

2.4.2.3.3 Vacuolar myelopathy. This subject will be considered in detail in chapter 2.5. 2.4.2.3.4 Peripheral nerve disorders. A variety of peripheral nerve disorders have been associated with the later stages of HIV-1 infection. They were seen in 16% of 331 AIDS patients and in 0.5% of 763 ARC patients that were followed up for 15 months (Fuller et al 1993). The commonest is a distal symmetrical peripheral neuropathy which is

predominantly sensory. Pain is a frequent feature, occurring in about 60% (Cornblath and McArthur 1988). It has been argued that some painful peripheral neuropathies may form a separate subgroup, probably related to CMV infection (Fuller et al 1989b, 1993), and that the non-painful subgroup may represent a heterogenous group with nutritional and other factors possibly being of relevance here. Other peripheral nerve syndromes include acute and chronic inflammatory demyelinating polyneuropathies (Cornblath et al 1987),

mononeuropathies (Lipkin et al 1985) and mononeuritis multiplex (McArthur 1987). Although HIV has been cultured from peripheral nerves (Cornblath et al 1987), and HIV- like particles observed intraaxonally (Bailey et al 1988), a definite aetiological association between HIV and peripheral nerve damage has not been established.

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26 2.5 MYELOPATHIES IN HIV-1 INFECTION

Spinal cord disease has been described in 41-48% of consecutive AIDS post mortems in two large series (Hénin et al 1992, Petito 1993). The commonest was vacuolar

myelopathy (see below), followed by infections (including HIV) and lymphoma. Infections occurred less frequently than in the brain, and were commonly seen in the context of similar infection in the brain.

A large prospective clinicopathological series of neurologically well documented myelopathies in HIV infection is lacking. Clinical evidence of myelopathy was described in 13/186 (7%) of HIV-infected patients referred for neurologic evaluation, of whom 12 had clinical evidence of vacuolar myelopathy and one had an acute myelopathy compatible with zoster myelitis (McArthur 1987). The clinical incidence is likely to be an

underestimate, since mild disease may not manifest clinically or myelopathy signs may be masked by concomitant intracerebral, brain stem or peripheral nerve disease.

I have chosen to include in the historical review of the vacuolar myelopathies references up to the time when the thesis was started and the questions and aims were posed (1991). In this way the reader may better understand the design of the studies reported later. The literature up to December 1996 is fully considered in the discussion and conclusions in the results chapters, and is summarised in detail in the tables at the end of this chapter (Tables 2.1, 2.2). The historical review of the non-vacuolar myelopathies includes literature up to December 1996.

2.5.1 Vacuolar Myelopathy (VM)

Snider et al (1983) first described a vacuolar myelopathy (VM) with axonal swelling and reactive astrocytosis in an AIDS patient with a paraparesis. Goldstick et al (1985) reported a similar patient with demyelination and spongy change of the lateral and anterior pyramidal tracts and posterior columns. Petito et al (1985) found VM in 20 of 89

consecutive AIDS post mortems, and provided the first definitive histological description. Goldstick et al (1985) and Petito et al (1985) noted the morphological similarity with subacute combined degeneration of the cord but they did not find vitamin B12 deficiency in their patients; folate levels were low in two of twelve patients tested.

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27 1990) and none of 15 in another (Dickson et al 1989). The prevalence of VM due to HIV- 2 infection is unknown.

2.5.1.1 Clinical aspects

Data from a large prospective clinicopathological study clearly defining the clinical spectrum, natural history, HIV related parameters, investigations, clinical associations, and survival in VM is lacking.

Retrospective pathological series and case reports suggest that VM frequently presents late in the course of HIV disease, with a duration of clinical AIDS of approximately 8-10 months (Petito et al 1985, Goldstick et al 1985, Ho et al 1985, Sharer et al 1990).

However, it has been described in a well HIV-seropositive patient without an AIDS diagnosis (McArthur 1987), as well as presenting concomitant with an AIDS defining illness (Ho et al 1985).

Clinical features frequently described have included a progressive paraparesis (Goldstick et al 1985, Petito et al 1985, Gabuzda et al 1986, Navia et al 1986a, Singh et al 1986, Guiloff et al 1988, Eilbott et al 1989, Grafe and Wiley 1989, Maier et al 1989, Rhodes et al 1989, Sharer et al 1990, Weiser et al 1990) or, less commonly, a monoparesis (Petito et al 1985, Navia et al 1986a), triparesis (Weiser et al 1990) or tetraparesis (Petito et al 1985, Navia et al 1986a, Navia and Price 1987), frequently with accompanying vibration and/or position sense loss (Goldstick et al 1985, Petito et al 1985, Singh et al 1986, Guiloff et al 1988, Grafe and Wiley 1989, Rhodes et al 1989). It was associated with a gait ataxia and/or a spastic bladder in some (Goldstick et al 1985, Petito et al 1985, Navia et al 1986a, Grafe and Wiley 1989). Some mild cases had only extensor plantar responses (Petito et al 1985). Petito also found a progressive dementia in 14 or her 20 cases, but found no correlation between the incidence and severity of the dementia and the severity of the myelopathy.

The results of investigations, where reported, have been normal or non-specific. Imaging studies of the cord (7 myelograms, 2 MRIs) have all been reported normal (Goldstick et al 1985, Petito et al 1985, Ho et al 1985, Singh et al 1986, Guiloff et al 1988, Sharer et al 1990). CSF studies, reported in 8 patients, showed normal cell counts and glucose in all patients (Snider et al 1983, Goldstick et al 1985, Ho et al 1985, Navia et al 1986a, Singh et al 1986, Navia and Price 1987, Maier et al 1989), mildly elevated protein (up to 0.74g/l) in four, and intrathecal synthesis of oligoclonal bands in one (Maier et al 1989).

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28 patients, but reported survival has ranged from 0.7 (Rhodes et al 1989) to 28 months (Gabuzda et al 1986).

A summary of the clinical features in published series is presented in table 2.1. 2.5.1.2 Pathology and unresolved pathological issues

Pathologically, VM is characterised by the presence of intramyelinic and periaxonal vacuoles (Petito et al 1985, Maier et al 1989), some containing macrophages, within the lateral, posterior and, less frequently, anterior columns of the spinal cord but not limited to specific tracts (Petito et al 1985).

The brunt of the pathology has been variously described as occurring in the mid and low thoracic levels (Goldstick et al 1985, Petitio et al 1985, Maier et al 1989), or high thoracic and cervical level (de la Monte et al 1987, Artigas et al 1990, Hénin et al 1992), leading to differing opinions as to its similarity with subacute combined degeneration of the spinal cord (Petito et al 1985, Artigas et al 1990).

Early descriptions of VM suggested a gradient of pathological severity, the posterior columns being worst affected rostrally and the lateral columns caudally (Goldstick et al 1985), a description reminiscent of a dying back phenomenon. Wallerian degeneration of the lateral corticospinal tracts has also been described in severely affected cases (Petito et al 1985). Ultrastructural studies have suggested that the mechanism of axonal damage may be axonal compression by the intramyelin sheath swelling (Petito et al 1985).

It is unclear whether gliosis is an integral part of the pathology of VM, as some report rare reactive astrocytes (Petito et al 1985) and others, intense astrogliosis (Artigas et al

1990).

A summary of imaging, CSF and pathological findings in published series is presented in table 2.2.

2.5.1.3 Theories o f Pathogenesis

The aetiopathogenesis of VM is unknown. At the start of this thesis the main hypotheses included (i) direct HIV-mediated cytopathogenicity, (ii) abnormalities associated with B 12/folate metabolism, (iii) immune-mediated mechanisms, and (iv) coinfection with an opportunistic agent.

(i) Direct HIV-mediated cytopathogenicity

The isolation of HIV-1 from the lumbar cord of two patients with myelopathy (Ho et al 1985, Gabuzda et al 1986) raised the possibility of a direct role for HIV-1 in the

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29 1989, Eilbott et al 1989, Rhodes et al 1989, Weiser et al 1990, Budka 1990), but not in others (Grafe and Wiley 1989, Rosenblum et al 1989, Artigas et al 1990, Kure et al

1991).

In addition, although VM appeared to occur frequently in patients with HIVE (Petito et al 1986), and vacuolar changes similar to that seen in the cord in VM had been described in cerebral white matter in some patients with AIDS in whom HIV infection in the brain has been demonstrated (Artigas et al 1989, Schmidbauer et al 1990), there was no clear association between cerebral HIV and VM (Rosenblum et al 1989). The occurrence of similar vacuolar myelopathy in several immunocompromised patients with no evidence of HIV-1 infection is also against a direct causal link with HIV (Kamin and Petito 1991). (ii) Abnormalities associated with B 12/folate metabolism

Both Goldstick et al (1985) and Petito et al (1985, 1986, 1994) noted the morphological similarity of VM to subacute combined degeneration of the cord, but neither found

abnormal serum vitamin B12 levels in their patients with VM (total 39 tested). Folate levels were low in only 2/39. Similar findings were later reported by other authors (Maier et al 1989, Rhodes et al 1989).

However, the identification of low levels of S-adenosylmethionine (SAM) (the main product of B 12/folate metabolism implicated in the pathogenesis of subacute combined degeneration of the cord) in the CSF of children with AIDS (Surtees et al 1990), raised the possibility that a cellular deficiency similar to that seen in inborn errors of B 12/folate metabolism may exist in patients with AIDS, thus predisposing them to the development of a myelopathy similar to subacute combined degeneration of the cord. Subsequent confirmation of low SAM levels in adult HIV seropositive patients, some of whom had myelopathy (Keating et al 1991) has lent some support to this theory.

(iii) Immune-mediated mechanisms

The relative paucity of identifiable HIV virus in relation to the degree of CNS damage in AIDS has lead to the suggestion that cytokines released by infected or activated

microglia, macrophages, multinucleated giant cells, or glia may be the primary mediators of CNS pathology (Meltzer et al 1990, Achim et al 1991). Myelin damage in the brain has been found to correlate with the extent of astrocytic and microglial reaction, and is accompanied in the early stages by a transient, presumably reactive, increase in

oligodendrocyte numbers (Esiri et al 1991).

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30 applied to the vacuoles (Petito et al 1985). Several macrophage derived products have been shown to be neurotoxic (Heyes et al 1991, Giulian et al 1990), but one in particular, TNFa, has been noted for its myelinotoxic properties (Sehnaj and Raine 1988).

(iv) Coinfection with an opportunistic agent

The occurrence of a similar vacuolar myelopathy in immunosuppressed patients without known HIV infection (Kamin and Petito 1991) has lead some authors to suggest the pathogenesis of VM may be linked to the immunosuppressed state (such as an associated infection, or coinfection with an as yet unidentified opportunistic viral virus).

2.5.2 Other myelopathies

The principal causes of myelopathies other than vacuolar myelopathy in two large pathological series of AIDS patients (Hénin et al 1992, Petito et al 1993), were HIV (5- 8%), CMV (4-5%), "fungal"/ cryptococcus (4%), lymphoma (2-3%), gracile tract degeneration (1-4%), and toxoplasmosis (1%). A "non-specific myelitis" (Hénin et al

1992) or microglial nodule myelitis (Petito 1993) was reported in 7% and 10%

respectively. The prevalence of other myelopathies was more variable, being reported in one series but not in the other. These included Herpes simplex (2%), Herpes zoster (1%), Mycobacterium tuberculosis (1%) (Petito 1993), corticospinal tract degeneration (2%), progressive multifocal leukoencephalopathy spinal cord lesions (1%) and microinfarcts of the cord (1 %) (Hénin et al 1992).

The following review is organised according to aetiology, beginning with infections (viral, bacterial, mycobacterial, fungal, protozoal), followed by neoplasms and

miscellaneous causes.

2.5.2.1 Infections

2.5.2.1.1 HIV myelitis. This is a pathological diagnosis defined by the presence of foci of MGCs, microglia and macrophages (as in HIVE) in the cord. In the absence of MGCs, the presence of HIV antigen or nucleic acids, as determined by immunocytochemistry or in situ hybridization, is required (Budka 1991, Hénin et al 1992). An associated HIV infection of the brain is commonly present.

HIV myelitis is distinct pathologically from vacuolar myelopathy, but they may coexist in the same individual (Petito et al 1994). It is more common than VM in children (Sharer et al 1990). However, its clinical manifestations in adults without concomitant VM have not been clearly defined.

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31 cough, drowsiness, and fever. He was found on admission to have a flaccid paraparesis, with depressed ankle jerks and extensor plantar responses without sensory signs. The CSF contained 10 lymphocytes, protein 0.63g/l and normal glucose. A myelogram was normal. He died a month later with peritonitis. At post mortem, there were multiple

granulomatous foci scattered throughout the spinal cord, with multinucleated giant cells, macrophages, microglia, microglial nodules and sparse lymphocytic infiltrates. The giant cells, macrophages and microglia were positive for HIV antigen on immunostaining. 2.5.2.1.2 HIV seroconversion and myelopathy

Myelopathy associated with primary HIV infection appears to be exceedingly rare. One case with an acute asymmetrical spastic paraparesis with bladder involvement and

lancinating back pains occurring 22 days after onset of symptoms of an HIV

seroconversion illness has been described (Denning et al 1987). In addition, his mentation was slow, and he had conjunctivitis, lymphadenopathy, hepatosplenomegaly, leucopenia and thrombocytopenia. He improved partially over two months. The CSF showed a lymphocytic pleocytosis of 7-24 cells/ml, protein of 0.68 g/1, and a normal glucose. HIV was isolated from blood and CSF lymphocytes. A myelogram was normal. Primary HIV infection was indicated by the rise in serum HIV antibody titre, the presence of IgM in serum and subsequent resolution of his haematological abnormalities. CSF HIV IgG was positive, but IgM was negative.

2.5.2.1.3 Cytomegalovirus

2.5.2.1.3.1 CMV myeloradiculopathy

Of twenty six patients with CMV related changes in the nerve roots/ganglia and spinal cord at post mortem, 25 presented acutely, with rapidly ascending, hypotonic lower limb weakness, leading to paraplegia over a median time of two weeks (range 4 days-4 weeks)(Moskovitz et al 1984, Tucker et al 1985, Bishopric et al 1985, Singh et al 1985, Eidelberg et al 1986, Morgello et al 1987, Behar et al 1987, Jacobson et al 1988, Vinters et al 1989b, Mahieux et al 1989, Budzilovich et al 1989, Bélec et al 1990, Chimelli et al

1990, de Cans et al 1990, Fuller et al 1990, Miller et al 1990, Marmaduke et al 1991, Said et al 1991, Cohen et al 1993). One further patient progressed subacutely (Budzilovich et al 1989). The lower limb reflexes were absent or depressed in 21/21, and 42% had urinary retention at presentation. Faecal incontinence was present in three (Tucker et al

1985, Singh et al 1996, Eidelberg et al 1986), lax anal sphincters in two (Jacobson 1988, Cohen et al 1993) and constipation in one (Belec et al 1990). Thirteen (50%) had evidence of systemic and/or retinal CMV infection.

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32 accompanying the motor dysfunction in ten (38.5%), It was described as shooting, shock­ like, radiating, or throbbing. An ascending sensory loss involving the sacral dermatomes was present in eight (31%).

Only a minority of the cases in the literature had clearly documented upper motor neurone signs despite changes in the spinal cord at post mortem, probably because they were masked by severe lumbosacral nerve root involvement. Two had extensor planter responses (Behar et al 1987, Fuller et al 1990), and one, developed contractures of the upper and lower limbs (Moskovitz et al 1984). Five (19%) had low thoracic sensory levels (T12-T10) (Tucker et al 1985, Jacobson et al 1988, Miller et al 1990, Cohen et al 1993).

The spinal cord changes described affected predominantly the lower lumbar and sacral segments and the conus, and included the presence of cells with CMV Cowdry type A inclusions, microglial nodules, lymphocytic infiltration, focal gliosis, central chromatolysis of anterior horn cells, subpial demyelination and/or necrosis, occasionally described as haemorrhagic (Morgello et al 1987), inflammation at the root entry and exit zones, and secondary degeneration of the gracile tract. One patient had a severe necrotising

meningomyeloradiculitis with microvascular thromboses (Vinters et al 1989b), and another had a severe necrotising encephalomyeloradiculitis (Marmaduke et al 1991). Cystic

changes were described in the spinal cord of one patient (Moskovitz et al 1984). In the roots, the pathological changes included focal or extensive necrosis,

demyelination, fragmentation, Wallerian degeneration, occasional thrombosis of blood vessels, lymphocytic infiltration and occasional CMV cells with typical inclusions. Ganglionitis with increased nodules of Nageotte was sometimes seen (Tucker et al 1985).

Improvement was most commonly reported with ganciclovir (Fuller et al 1990, Belec et al 1990, de Cans et al 1990, Miller et al 1990, Marmaduke et al 1991, Said et al 1991, Cohen et al 1993). Of two patients given foscarnet after failing to respond to ganciclovir, one improved transiently (Jacobson et al 1988), whilst another continued to progress (de Cans et al 1990).

The median survival from onset to death was 6.25 weeks (range 3 weeks-8 months). The two patients surviving eight months had both been treated with ganciclovir (Cohen et al 1993).

The CSF frequently showed a pleocytosis ranging from 9 (Cohen et al 1993) to 3400 (Tucker et al 1985) white cells/mm\ commonly with a polymorphonuclear cell

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33 "normal" (Fuller et al 1990, Said et al 1991) to 6.6g/l (Bishopric et al 1985), glucose was frequently low, being less than 2 mmol/1 in 50% of cases (range 0.74 mmol/1 (Chimelli et al 1990) to "normal" (Said et al 1991). Positive CSF cultures for CMV are helpful, but negative cultures are seen even among pathologically proven cases (Vinters et al 1989b, Miller et al 1990). PCR for CMV DNA in the CSF appears useful for early diagnosis; good responses to anti-CMV treatment in patients diagnosed this way have been reported (Cohen et al 1996).

Imaging studies were normal in 12/13 pathologically confirmed cases; one showed arachnoiditis of the lumbar roots (de Cans et al 1990).

2.5.2.1.3.2 CMV "pure" myelopathy

Four cases of "pure" CMV myelopathy with pathological confirmation have been described (Moskovitz et al 1984, Vinters et al 1989b, GÜngôr et al 1993, Moulignier et al

1996). The documentation of neurological signs was limited. One had inability to walk attributed to his general debility, diffusely diminished power, and preserved and symmetrical reflexes. Sensation was not examined. Post mortem revealed cytomegalic cells and CMV inclusions in the posterior columns of the mid-thoracic cord and mild degeneration of the posterior and lateral corticospinal tracts in the lumbar cord (Moskovitz et al 1984). Another had "findings suggestive of intrinsic spinal cord abnormalities". He improved on treatment with ganciclovir after CMV was isolated from his CSF. At post mortem, foci of "old" necrotizing myelopathy in the thoracolumbar spinal cord was found. However, in situ hybridisation studies for CMV and HSV were negative (Vinters et al

1989b). The third was a seven year old child perinatally infected with HIV who developed tremor, ataxia and generalised spasticity at the age of 4.5 years. Two years later, the upper limbs became flaccid and she developed sphincter involvement. She had CMV retinitis. MRI revealed a cystic inflammatory lesion from C2-7. She did not respond to ganciclovir. Post mortem revealed a necrotising myelitis affecting irregular areas of white matter along the length of the cord. CMV inclusions were seen in the lesions and CMV antigen confirmed by immunohistochemistry (GÜngôr et al 1993). The fourth had an acute paraplegia with lower limb areflexia and urinary retention, preceded by severe burning pain in the feet for two weeks. The left planter response was extensor. MRI showed enlargement of the conus medullaris with a central rim-enhancing lesion, the CSF showed 120 white cells/mm^ (90% polymorphonucleocytes), a protein of 0.56g/l, and glucose of 2.2 mmol/1. PCR was positive for CMV in the CSF. He improved on

Figure

Table 2.1. Literature review. Vacuolar myelopathy - Clinical features
Table 2.2 Literature review. Vacuolar myelopathy - Investigations and pathology.
Table 5.1 Protocols for CT scans of the head and spine.
Table 8.1 Sequential admissions. Neurological symptoms and signs.
+7

References

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