A NEUROLOGIST S APPROACH TO THE IMMUNOSUPPRESSED PATIENT

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1 A NEUROLOGIST S APPROACH TO THE IMMUNOSUPPRESSED PATIENT ACQUIRED See end of artile for authors affiliations Correspondene to: Dr I Ormerod, Department of Neurology, Frenhay Hospital, Bristol, UK; ian.ormerod@ north-bristol.swest.nhs.uk I CDougan,IOrmerod J Neurol Neurosurg Psyhiatry 2004; 75(Suppl I):i43 i49. doi: /jnnp t is not unusual to be asked for a neurologial assessment of a patient with some form of immune suppression. Most patients will have an aquired disorder of the immune system and are the fous of this review (table 1). We shall not disuss the neurologial onsequenes of HIV, as this is the subjet of a separate artile in this supplement (see p i29), nor those with rarer inherited immune defiieny as their investigation and treatment is suh a highly speialised area. IMMUNE SUPPRESSION Aquired immune suppression may be a deliberate goal of medial treatment where the aim is to redue an inappropriate immune response, suh as treating myasthenia with steroids and azathioprine. It may be a reognised undesired effet of treatment for another ondition for example, in a patient on anti-neoplasti hemotherapy. Less obviously immunosuppression an our in disorders that impair the effetiveness of the immune system for example, systemi lupus erythematosus (SLE), diabetes, renal failure. In all these situations the ondition being treated with immunosuppression, or the proess ausing the immune suppression, may have their own inherent neurologial manifestations additional to suppression of the immune response. Examples inlude non-metastati effets of malignany, suh as limbi enephalitis, or a systemi ondition suh as SLE that leads to diret involvement of the entral nervous system (CNS) presenting as neuropsyhiatri illness. Alternatively, treatments for malignany also have diret and unwanted effets on the CNS and neuromusular system for example, the neurotoxi side effets of ytotoxi drugs. Immunosuppression hanges the normal relationships to the miroorganisms so: innouous organisms in the immune ompetent individuals beome pathogeni infetions evolve rapidly the usual linial and laboratory manifestations and markers of infetion may not be seen or deteted. This alters the linial presentation and features of infetion, both systemi and neurologial. Immunosuppressed patients are suseptible to a variety of general medial problems relating to the underlying illness, systemi infetion, adverse effets of drugs, poor nutrition, and the medial interventions to whih they are exposed. Thus, in the immunosuppressed patient with neurologial involvement there are three inter-related areas to onsider. First, has whatever aused the immunosuppression either diretly or indiretly affeted the nervous system? Seond, are suh problems due to an infetion of the nervous system? And last, are there any medial ompliations that might produe a neurologial disturbane? In assessing immunosuppressed patients, the liniian must remember that more than one of these fators may be involved in the neurologial presentation. These patients are often overtly unwell and obtaining information from other medial attendants, the general pratitioner, other health professionals, and the patient s family is essential for proper evaluation. You will often be dealing with a ondition or treatment with whih you will have little familiarity. Therefore disussion with the mirobiologist, onologist, haematologist, linial immunologist, other speialists involved in the are of the patient, as well as with the hospital pharmaist/drug information servie is required. Some questions to ask yourself at the bedside are given in box 1. CAUSES OF IMMUNE SUPPRESSION: HOST FACTORS The lassifiation of immune defiient onditions is given in table 1. We shall fous, using the linial approah outlined in box 2, on the more ommon aquired immune onditions and disuss eah of these in turn, although many of the priniples apply aross all immunodefiient states. i43 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.

2 i44 Table 1 Classifiation of immune defiient onditions Primary/inherited immune defiieny states Antibody defiieny Combined antibody and ellular immunodefiieny Complement defiieny Seondary/aquired immune suppression (non-hiv) Extremes of age Diabetes Chroni aloholism Connetive tissues disease Organ failure (renal failure, hepati failure) Malignany (espeially haematologial and lymphoretiular) Iatrogeni hemotherapy radiotherapy transplantation Asplenism/spleni dysfuntion (primary or seondary for example, sikle ell disease, trauma) DIABETES Patients with diabetes have an inreased risk of erebral vasular disease. Diabetes is assoiated with various types of neuropathy (see Llewelyn 1 in this series) and auses retinopathy. In addition there are ompliations assoiated with more aute metaboli disturbane related to hypoglyaemia and hyperglyaemia. Patients with diabetes are prone to infetions whih may be related to high irulating levels of gluose and to ompromised vasular irulation. Two unommon but well reognised and typial infetions of the head in diabetes are rhinoerebral muormyosis and malignant otitis externa. Rhinoerebral muormyosis Fifty per ent of rhinoerebral muormyosis fungal infetion ours in the ontext of diabetes, and in half of these the presentation is in the ontext of ketoaidosis. The infetion an involve nose, paranasal sinuses, orbit, and brain. Faial and oular pain are ommonly present and the patient may develop orbital swelling with proptosis and ophthalmoplegia. Neroti lesions on the palate are harateristi. The infetion tends to spread along vasular hannels. Diagnosis is usually onfirmed with biopsy (fig 1). Surgial treatment ombined with amphoteriin is reommended. Some authorities have suggested hyperbari oxygen treatment. Malignant otitis externa Malignant otitis externa is an infetion whih starts in the skin and the external ear anal. The majority (80%) of patients are diabeti. The infetion may then spread from the ear to the soft tissues and bone of the skull base. Cranial nerve palsies VII through to XII may result. The infeting agent is usually Pseudomonas aeruginosa. Patients present with otalgia and evidene of infetion in the external auditory anal. The extent of spread may be shown with omputed tomography (CT) or magneti resonane imaging (MRI) with views of the skull base. Debridement followed by appropriate antibiotis (peniillin with ephalosporins suh as eftazidime). CHRONIC ALCHOLISM Patients with hroni aloholism often have poor nutrition and an have redued granuloyte funtion with onsequent suseptibility to nutritional syndromes and baterial infetions. In addition they may have lotting disorders. Box 1: Some questions to ask yourself at the bedside Is this patient immune suppressed? Sometimes this will be obvious but in other patients a review of the past medial history may be an important starting point. As outlined above, the spetrum of illness assoiated with immune suppression is wide and that the patient is immunosuppressed may not be immediately obvious. What is the neurologial problem? Again this may not be easy. Patients may be unwell and have multiple medial problems. The neurologist is sometimes alled in when the liniians in harge are in diffiulties. The ontext of the examination may be unfamiliar to you for example, in the transplant unit, making an assessment more diffiult with the patient attahed to omplex equipment. Is this a general medial problem? It is important to exlude metaboli disturbane, hypoxia, sepsis, or organ failure as a primary ause. It is always worth onsidering prompt administration of intravenous vitamin supplements (thiamine, riboflavin, and pyridoxine) in the malnourished patient. Is this some treatable infetion? Clearly this is something not to be missed. When investigations are requested it is essential to involve the mirobiologist so that orret samples are sent and appropriately proessed. Awareness that ertain types of infetion may be signatures of partiular illnesses is helpful. An example would be rhinoerebral muormyosis in diabetes. Is this a neurosurgial problem? Again, not to be missed. Is there evidene of a erebral mass lesion or evidene of ord ompression? Sanning of patients who are unwell, restless, and agitated an be problemati. Enhaned imaging with ontrast may be useful and engaging the radiologist in disussing the problem helpful. Is the linial piture aused by the underlying medial ondition? Could reurrent malignany or a paraneoplasti syndrome explain the problem? Is the problem a reognised presentation of the underlying medial problem, suh as vasulitis? NEUROLOGY IN PRACTICE Is this a diret side effet of therapeuti agents? There are adverse effets, other than immune suppression assoiated with hemotherapy and radiotherapy. Some of these drugs may be unfamiliar to you. Cheking them with the pharmay or your drug information servie is advisable. Box 2 A linial approah to the immune suppressed patient Consider The speifi ompliations of the primary diagnosis The potential side effets of its treatment The ompliations of an impaired immune response unusual presentation of infetion with ommon pathogens infetion with unusual pathogen (opportunisti infetions) The general medial health of the patient The speifi nature of infetion, as some are antiipated in partiular onditions (for example, malignant otitis externa in diabetes). J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.

3 NEUROLOGY IN PRACTICE Figure 1 Case history. A 48 year old male patient with diabetes mellitus who developed a sore throat and fever while abroad, subsequently developed a swollen painful nose, and a flutuating level of onsious. On return to the UK there was gangrene of the nose, loss of vision, and ophthalmoplegia. A CT san showed swelling of the frontal lobes, and angiography suggested an arteritis. Muormyosis was isolated from the skin. His ondition deteriorated and he died 17 days after onset of illness. At neropsy there was involvement of the midline strutures of the fae, the orbits, and extension into the brain. (A) Inferior aspet of frontal lobes. Note haemorrhagi defet of the right gyrus retus. (B) Low power of wall of absess in right frontal lobe. There is a mixture of neroti debris, mononulear inflammation ells, and multinuleated giant ells. Haematoxylin & eosin (C) Hyphae of muor. Silver impregnation (Figs ourtesy of Professor DI Graham). CONNECTIVE TISSUE DISEASE Connetive tissue diseases an affet the nervous system in a variety of ways (table 2). This may be by diret involvement in the inflammatory proess, suh as vasulitis, or indiret involvement mediated by irulating antibodies. The presene Box 3: Neurologial ompliations of organ failure Renal failure Dialysis ompliations (dysequilibrium syndrome, dialysis enephalopathy) Nutritional syndromes Compliations of antioagulation Transplantation enephalopathy Uraemi enephalopathy Hepati failure Hepati enephalopathy Coagulation defets Nutritional defets of anti-phospholipid antibodies is assoiated with a prothromboti tendeny and inreased risk of erebral or retinal ishaemia. These antibodies may be found in SLE or as part of the primary anti-phospholipid antibody syndrome (APS). Patients with SLE may have multiple omplement defiienies with onsequent risk of infetion. Furthermore, neurologial ompliations may be seondary to treatment with steroids or other immunosuppressants (see later). ORGAN FAILURE Renal failure Dialysis dysequilibrium syndrome is aused by an osmoti gradient between plasma and brain ourring with dialysis and resulting in erebral oedema and enephalopathy (box 3). Patients develop headahe and may go on to develop oma, seizures, and myolonus. Dialysis enephalopathy is a progressive entral nervous system (CNS) disorder whih may be related to aluminium aumulation. Patients develop ataxia, myolonus, and progressive ortial dysfuntion (dyspraxia, dysphasia, dysgraphia) and later onvulsions. Treatment onsists of prevention of aluminium exposure and helation in established ases. In ommon with other onditions ausing poor nutrition, Wernike s enephalopathy an be seen in patients with renal failure. Dialysis and gluose loading may preipitate aute thiamine defiieny. Uraemia, ombined with antioagulation for treatment, may lead to bleeding suh as subdural haematoma. Transplantation enephalopathy may be seen in the early months post-transplantation, presenting with headahe, onstitutional symptoms, and sometimes seizures. This is thought to be a self limiting illness with an immunologial basis. Compliations of the immunosuppressive agents used in transplantation infetions and seondary malignany (typially lymphoretiular) are disussed later. Box 4: Treatments ausing immune suppression Steroids Other immune suppressant drugs Anti-neoplasti drugs Monolonal (anti-lymphoyte) antibodies Radiotherapy Transplantation i45 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.

4 i46 Table 2 Neurologial ompliations of onnetive tissue diseases Connetive tissue disease Brain Neuropsyhiatri Cord Hepati failure Patients with impaired liver funtion may develop enephalopathy. Shunting from the portal into the systemi irulation may ontribute to this. This an ome on quikly and resolve rapidly. Foetor, a metaboli limb flap, and triphasi EEG waves may help in the diagnosis. Coagulation defets may lead to bleeding ompliations. Patients with hepati dysfuntion may be partiularly prone to nutritional defiieny. Although the B vitamins are the most ommon ause of neurologial syndromes, patients with gastrointestinal malabsorbtion may develop vitamin E defiieny whih is assoiated with ataxia, ophthalmoplegia, and peripheral neuropathy. COMPLICATIONS OF IMMUNOSUPPRESSIVE TREATMENT The drugs that either intentionally or unintentionally produe immunosuppression (box 4) an have other adverse effets on the nervous system. These need to be reognised and distinguished from ompliations of immunosuppression. Cortiosteroids (steroids) and other immune suppressants Steroids an be administered orally as prednisolone or dexamethasone or intravenously as dexamethasone or methylprednisolone. Adverse effets are shown in box 5. A variety of immune suppressant drugs are used, often with steroids, to modify an abnormal immune response. Azathioprine is perhaps the most frequently used drug in neurologial pratie, but other ommonly used drugs inlude methotrexate, ylophosphamide, and ylosporin. Some of these drugs have diret neurologial ompliations (table 3). Antineoplasti drugs The adverse effets of antineoplasti drugs are given in table 3. Radiotherapy Radiation therapy auses neurologial ompliations in a number of ways. The effets will depend to an extent on dose, frationation, and radiation field. Radiotherapy given widely Peripheral neuropathy Musle Other SLE RA Nodules ausing ompression Sjogren s syndrome + + Trigeminal neuropathy, myositis Systemi slerosis Myositis Wegener s granulomatosis RA, rheumatoid arthritis; SLE, systemi lupus erythematosus. Box 5: Compliations of steroid treatment Diabetes Immune suppression Eletrolyte disturbane Psyhosis/depression Myopathy Osteoporosis Avasular nerosis of the hips may affet the immune system by damaging the bone marrow and other immunologially ative tissues. Speifi problems from CNS irradiation may be aute or delayed. Below are some of the more ommonly enountered problems: Drowsiness, anorexia, and nausea are ommon in patients undergoing ranial irradiation Aute enephalopathy may be seen with erebral swelling giving headahe and progressive neurologial deterioration. Treatment with steroids is helpful Delayed ranial nerve damage may be seen inluding opti neuropathy and sensori-neural deafness. Pituitary failure an also develop similarly Subaute demyelination ourring within months of treatment and presenting with neurologial deterioration may again be helped by steroids Radiation nerosis may present years after treatment and differentiation from tumour an be diffiult. The ause is unertain but pathologial hanges our in small blood vessels Long term white matter damage an present with progressive neurologial and ognitive deline. This presentation may be more ommon in patients who also reeived hemotherapy. The imaging features are of progressive atrophy and diffuse white matter hange. Transplantation The suess of organ transplantation requires effetive immunosuppressive hemotherapy. The ompliations of renal transplantation have already been disussed. There are more speifi, ommon ompliations assoiated with bone marrow transplantation. Fifty per ent of patients who undergo bone marrow transplant have neurologial ompliations and a signifiant number (5 10%) will die from these. The neurologial ompliations are shown in box 6 in order of inidene. Box 6: Neurologial ompliations of bone marrow transplantation NEUROLOGY IN PRACTICE Metaboli enephalopathy hypoxia hepati failure renal failure eletrolyte imbalane Infetion early (, 1 month): baterial, viral, fungal late (1 12 months): viral, parasiti Cerebrovasular ompliations seondary to infetive or non-infetive endoarditis Malignany Post-transplantation lymphoproliferative (Ebstein-Barr virus indued) disorders Reurrene of original tumour J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.

5 NEUROLOGY IN PRACTICE Table 3 Neurologial ompliations of immune suppressive and anti-neoplasti treatment Drug Enephalopathy Seizures Neuropathy Ataxia Other Alkylating agents + BCNU + Cisplatin + Deafness Cylosporine Hemiparesis, paraparesis Cytosine arabinoside + 5-Flurourail + + L-asparginase + Coagulopathy, venous sinus thrombosis Methotrexate (MTX) Leuoenephalopathy, meningitis (with intratheal MTX) OKT3 antibody + Asepti meningitis Steroids Psyhosis, myopathy Tarolimus Taxol + Vinristine + BCNU, bishloroethylnitrosourea. CNS INFECTION The approah to the diagnosis of infetion in immunosuppressed patients differs from that in usual linial pratie. Presentations may be subtle or atypial beause of an altered inflammatory response, and some of the investigations will be of limited utility. An elevated white ell ount may not be seen in patients who are neutropeni or immunosuppressed. The erythroyte sedimentation rate (ESR) may be of little use as this is a rude measure of fibrinogen whih may be redued in hepati disease and in patients with oagulopathy. Treatment should be based on identifiation of the organism and seletive appropriate antibiosis; however, this may not be possible in the first instane in a patient who is severely unwell, and empirial treatment may be required so knowledge of the likely infeting pathogen(s) is useful. In this situation advie from the mirobiologist is invaluable. Bateria, viruses, fungi and parasiti infetions need to be onsidered and investigated (box 7). CNS INFECTION BY LOCATION It is useful linially to onsider the likelihood of the pathogen depending on the linial syndrome (table 4). SOME SPECIFIC INFECTIONS Candida albians Candida albians is a ommon infetion in patients with defetive granuloytes. Disseminated infetion may affet many organs inluding the CNS. Clinial presentation may sometimes be similar to baterial sepsis with systemi manifestations. CNS infetion may be introdued by instrumentation inluding lumbar punture (LP). C albians may ause meningitis and erebral absess with a high mortality rate. Cryptoous neoformans Cryptoous neoformans is a ommon ause of fungal meningitis in immunoompromised patients, espeially in those Box 7: CNS infetions in the ompromised host Bateria: Listeria monoytogenes, Noardia, Staphyloous aureus, Pseudomonas aeruginosa, Myobaterium tuberulosis Fungi: Cryptoous neoformans, Aspergillus fumigatus, Zygomyetes (Muor and Rhizopus), Candida albians Viruses: variella zoster, herpes simplex, ytomegalovirus Parasites: toxoplasmosis, strongyloides with ell mediated immune defiits suh as organ transplantation, lymphoma, or HIV. Onset may be insidious and headahe is often present; however, fever may not be a feature. CSF is usually lear and typially reveals a lymphoytosis, low gluose, and elevated protein level. A definitive diagnosis relies on positive ulture; however, rypotooal infetion an be suspeted earlier by diret examination of the CSF on India ink stain, whih has a sensitivity of 50%, or, if apsular antigen is present, on latex agglutination testing, whih has a sensitivity of 95%. Treatment is with ombined amphoteriin B and 5 flouroytosine. C neoformans may also ause erebral or spinal absess. Listeria monoytogenes Listeria monoytogenes infetion is often diagnosed after delay. The bateria may ause meningitis, meningoenephalitis, infetion of the brain stem (rhomboenephalitis), and rarely erebritis or absess formation. Reurrent or relapsing listerosis an our in immunoompromised individuals. Diagnosti delay is often aused by lak of linial suspiion or the organisms being dismissed as laboratory ontaminants. Here the peripheral white ell ount may be misleadingly normal. Clinial presentation of listeria meningitis is as a febrile illness with impairment of onsiousness in most ases (box 8). In about 75% of ases, CSF shows a predominant neutrophilia but frequently with a mixed lymphoyti and monoyti piture. In the remaining 25% lymphoytes or monoytes predominate. CSF gluose is often normal, but the protein usually raised. The organism may be ultured from blood in 75% and CSF in 80% of ases. Repeated blood ultures an be helpful in establishing the diagnosis. Serum antibody titres for listeria are unreliable as these an be present at high levels in individuals with no ative infetion. Treatment is normally with ampiillin for at least two weeks (in immunoompromised patients three to four weeks Box 8: Clinial neurologial findings in CNS listeria infetion Impaired onsiousness Seizures Cranial nerve palsy (III XII) Cerebellar signs Foal weakness i47 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.

6 i48 Table 4 Pathogens based on CNS loation is reommended). Other antibiotis, inluding o-trimoxazole and vanomyin, have been used where peniillin sensitivity exists. In the pre-antibioti era mortality exeeded 66%, and the mortality remains high despite urrent antibiotis at 20 30%; 10% of survivors have neurologial defiits whih may improve further after resolution of the infetion. INVESTIGATION OF SUSPECTED INFECTION IN THE IMMUNOSUPPRESSSED PATIENT Investigation of CNS infetion After imaging to exlude a mass lesion, CSF should be examined (box 9) provided there are no other ontraindiations (for example, disordered oagulation). Often the laboratories will have to be direted to look for the speifi organisms depending on linial suspiion. The differential may be wide and may inlude malignany. It is often useful to store extra CSF that an be re-examined later for additional speifi tests. Repeat LP may be useful for deteting malignant ells or monitoring response to treatment. Further investigation It is important to look for systemi manifestations of CNS infetion suh as atypial pneumonia. A thorough history and physial examination should help, inluding aurosopy and skin examination. Patients should have swabs, ulture, and biopsy of any skin lesions. Also a hest x ray, blood ultures, serology, throat swabs, and urine ulture are essential. GENERAL MEDICAL CAUSES OF NEUROLOGICAL COMPLICATIONS Remember that many patients who present neurologially may have a general medial ondition. These are listed in box Box 9: CSF examination in the immunoompromised patient Bateria Fungi Parasites Viruses Meningitis Listeria, enteri bailli Cryptoous Toxoplasma Variella zoster Pneumoous Candida Strongyloides Herpes Meningoous Coidioidomyosis Coxsakie Haemophilus Meningoenephalitis Listeria Aspergillus Toxoplasma Variella zoster Legionella Cryptoous Strongyloides Herpes Enteri bailli Muor Papovavirus Absess Noardia Cryptoous Toxoplasma Papovavirus Enteri bailli Aspergillus Staphyloous Candida Streptoous Opening pressure Protein Red blood ell/white blood ell (ell type and ount) Gluose (and blood gluose) Cytology Baterial stains and ulture Fungal stains and ulture AFB (aid fast bailli) Cryptooal antigen Viral PCR (polymerase hain reation) and ulture Immunoytohemistry (when malignany suspeted) 10 and an be a useful heklist when no speifi neurologial features an be found. APPROACH TO THE ENCEPHALOPATHIC PATIENT Perhaps one of the most ommon linial problems is the enephalopathi patient who is onfused and drowsy and may have other neurologial features suh as seizures. The linial approah is similar to the general sheme outlined above and is summarised in fig 2. Having exluded general medial type problems the neurologial aspets of the ase need to be interrogated. Cerebral imaging (preferably MRI with gadolinium ontrast) is helpful. It is often diffiult to obtain good quality sans in onfused and agitated patients. If thought normal, sans may need to be reviewed by a speialist neuroradiologist or repeated depending on other investigations and linial progress. In the immune suppressed patient the piture an hange quikly. If there is no Box 10: General medial auses of neurologial ompliations NEUROLOGY IN PRACTICE Metaboli eletrolyte or aid/base imbalane hypoxia/hyperapnia hyperglyaemia/ hypoglyaemia Cardia endoarditis (infetive or sterile) Respiratory atypial pneumonia pulmonary emboli Gastrointestinal hepati failure panreati enephalopathy malabsorption/nutritional syndromes Musuloskeletal osteomyelitis septi arthritis Inflammatory/autoimmune diseases onnetive tissue diseases vasulitides Malignanies espeially haematologial and lymphoretiular Endorine phaeohromoytoma/arinoid Addison s disease thyroid disease parathyroid disease Toxiity drugs and drug withdrawal presribed or illiit J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.

7 NEUROLOGY IN PRACTICE Figure 2 Flow hart showing an approah to assessment of the enephalopathi patient. ontraindiation to CSF examination this should be done. In ollaboration with the linial mirobiologist, analysis for usual and opportunisti infetions should be arried out and inlude PCR examinations (for example, herpes simplex) and antigen tests (for example, ryptooal antigen). Fresh samples for ytologial examination should be taken. Again, in pursuit of a diagnosis, the CSF examination may need to be repeated. CONCLUSION Diagnosis of the neurologial ompliations in immunosuppressed patients an be a hallenging but rewarding task for the neurologist. Knowledge of the likely auses with aggressive treatment of defined or suspeted infetion is warranted, as these patients an deteriorate rapidly. In those who elude diagnosis, medial ompliations or speifi effets of treatment should be onsidered. Seeking speialist help from olleagues in other disiplines is invaluable in the diagnosis and management. ACKNOWLEDGEMENTS We are grateful to Professor DI Graham for fig Authors affiliations C Dougan, I Ormerod, Department of Neurology, Frenhay Hospital, Bristol, UK REFERENCES 1 Llewelyn JG. The diabeti neuropathies: types, diagnosis and management. J Neurol Neurosurg Psyhiatry 2003;74(suppl II):ii Zunt JR. Central nervous system infetion during immunosuppression. Neurologial Clinis 2002;20:1 22. This paper summarises infetions in the immunosuppressed host with HIV or post-transplantation. The summary tables and diagnosti utility of investigations are partiularly helpful. 3 Conti DJ, Rubin R. Infetion of the entral nervous system in organ transplant reipients. Neurologial Clinis 1988;6: This paper emphasises the timing of likely pathogens posttransplantation and disusses eah of the infeting pathogens. 4 Bartt R. Listeria and atypial presentations of listeria in the entral nervous system. Semin Neurol 2000;20: A omprehensive overview of Listeria infetion. 5 Davis DG, Pathell RA. Neurologi ompliations of bone marrow transplantation. Neurologial Clinis 1988;6: This paper highlights the frequeny of neurologial ompliations in bone marrow transplant patients. 6 Keime-Guibert F, Napolitano M, Delattre J. Neurologial ompliations of radiotherapy and hemotherapy. J Neurol 1998;245: Shapiro WR, Young DF. Neurologial ompliations of anti-neoplasti therapy. Ata Neurol Sand 1984;70(suppl 100): Burn DJ, Bates D. Neurology and the kidney. J Neurol Neurosurg Psyhiatry 1998;65: An invaluable reminder of the neurologial ompliations of renal disease. 9 Overturf GD. Indiations for immunologial evaluation of patients with meningitis. Clinial Infetious Diseases 2003;36: This paper reviews the pathogens that ause meningitis and addresses the question of who should go on to have further immunologial testing. 10 Min DI, Monao AP. Compliations assoiated with immunosuppressive therapy and their management. Pharmaotherapy 1991;11:119S 25S. A useful overview of the speifi and general ompliations of the ommonly used immunosuppressants. 11 Rubin RH, Young LS. A linial approah to infetion in the ompromised host, 2nd ed. Boston: Kluwer Aademi/Plenum Medial, For referene only, but one for the library or to borrow from your mirobiologist s shelf. i49 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 29 April 2018 by guest. Proteted by opyright.