1. Education
Basic Medical Qualification
University Attended: University of Science Malaysia
Degree Obtained: Doctor of Medicine (MD)
Date Awarded: 25th July 1999
MRCP (Member of the Royal College of Physicians)
Date Awarded: 22nd July 2003
2. Working Experience and Present Appointment
July 1999-October 2000
• Commenced internship training in Sultanah Aminah Hospital Johor Bahru
(HSAJB), Malaysia
• Underwent 18 months training in General Medicine, General Surgery
(Including Plastic Surgery, Urology, Neurosurgery and Paediatric Surgery),
Obstetrics and Gynaecology, Orthopaedics and General Paediatrics.
November 2000-March 2001
• Joined the Department of Medicine HSAJB as a medical officer
• Commenced subspeciality rotation in Nephrology
April 2001-October 2001
• Haematology rotation
November 2001-March 2002
• Neurology rotation
April 2002-November 2002
• Infectious Disease and Intensive Medicine rotation
December 2002-July 2003
• Cardiology, Respiratory Medicine, Gastroenterology and Endocrinology
rotation
July 2003-December 2004
• Granted membership to the Royal College of Physicians of United Kingdom
• Assigned to a 35 bedded general medical ward as general physician in Sultanah Aminah Hospital Johor Bahru, Malaysia upon completion of MRCP
January 2005-June 2006
• Commencement of Nephrology Subspeciality Training
(Nephrology Followship Programme) in HSAJB
July 2006-December 2007
• Completion of Nephrology Subspeciality Training in Kuala Lumpur
Hospital, Malaysia
January 2008- February 2010
• Attached to the Nephrology Unit, Department of Medicine, HSAJB as Consultant Nephrologist and Physician.
February 2010 – to date
• Consultant Nephrologist and Physician,
Hospital Pantai Ayer Keroh
75450, Melaka
3. Registration as a Medical Practitioner
5th July 2000
• Full registration with the Malaysian Medical Council
12th November 2008
• Full registration with the General Medical Council of United Kingdom
4. Official Gazettement by the Government of Malaysia (Ministry of Health)
22nd January 2005
• Gazetted as a Internal Medicine specialist
1st January 2008
• Gazetted as a Nephrologist
5. Professional Activities
2003
Clinical attachment in the New Royal Infirmary of Edinburgh, Scotland
Department of Nephrology
Position: Visiting Registrar
Supervisor: Dr Robin Winnie
Consultant Nephrologist
New Royal Infirmary of Edinburgh
Edinburgh
2008
Attended the Malaysian Nephrology Board Examination on 9th May 2008
Conducted by the Nephrology Board Malaysia
(Malaysian Society of Nephrology, Ministry of Health Malaysia, Academy of
Medicine, Malaysia)
Obtained the highest marks in the 2008 cohort
2008-2009
Awarded a full scholarship by the Public Services Department of Malaysia to
pursue a one year advance nephrology training in the field of vasculitis in Addenbrooke’s Hospital Cambridge University Hospitals NHS Foundation Trust
Position: Honorary Clinical Research Fellow
Supervisor: 1) Dr David Jayne
Director of Lupus and Vasculitis,
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust
2) Professor Kenneth Smith
Cambridge Institute of Medical Research,
University of Cambridge,
United Kingdom.
2008- 2010
Coordinator for National Glomerulonephritis Registry, National Renal Registry
(Johor Bahru)
6. Professional Bodies
National
Member of the Malaysian Medical Association
Member of the Malaysian Society of Nephrology
Member of the Postgraduate Renal Society, Malaysia
International
Member of the Royal College of Physicians of Edinburgh
Member of the International Society of Nephrology
Member of the IgA International Network
7. Research Activities
Publications:-
Acute renal failure in the same hospital 10 years apart; A comparison of two prospective studies in Sultanah Aminah Hospital, Johor Bahru
Medical Journal of Malaysia Vol 62 No1 March 2007
Lactic acidosis in HIV patients receiving highly active antiretroviral therapy- the Johor Bahru experience
Medical Journal of Malaysia Vol 62 No 1 March 2007
Quality improvement in Department of Nephrology, Kuala Lumpur Hospital- an audit on clinical performance indicators
Journal of Quality Improvement Vol 10 No 2 2007
Rituximab in Behcet’s Disease
Submitted to Annals of Rheumatic Diseases for publication (May 2009)
Participation in clinical studies:-
National
HDP study- Hospitalisation rate among Dialysis Patients study (2007)
International
GIANT study- Greatest International Antibiotic Trial study (2006)
A randomized double blind placebo controlled multicenter study to evaluate the efficacy and safety of two doses of Ocrelizumab in patients with WHO or ISN Class III or IV nephritis due to systemic lupus erythematosus (2008)
A phase III multicentre, double blind, double dummy, randomized flexible dose comparative study of MCI-196 versus Simvastatin for the treatment of dyslipidaemia in subjects with chronic kidney disease on dialysis (2009)
Evaluation of chronic kidney disease patterns through the global information database (GRID) (2009)
Biologic therapies in neuro-behcet’s disease, an international collaborative case-series- neurobehcet study group, International Society of Behcet’s Disease (2009)
CHiC-TRIAD (Cambridge Hinxton Centre for Translational Research In Autoimmune Disease) (2008-2009)
MY-CYC (A randomised clinical trial of mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA associated vasculitis) (2008-2009)
Abstracts:-
National
OUTCOME OF A COMMUNITY BASED HEALTH SCREENING PROGRAMME DURING THE PUBLIC AWARENESS CAMPAIGN ON KIDNEY CARE IN JOHOR BAHRU, MALAYSIA
Oral Presentation- 22nd MSN Annual Seminar in Nephrology
Prevention of Chronic Kidney Disease
MYCOPHENOLATE MOFETIL IN RELAPSING LUPUS NEPHRITIS
23rd Malaysian Society of Nephrology Annual Seminar
Johor Bahru, Malaysia
11-13th April 2007
MYCOPHENOLATE MOFETIL IN MEMBRANOUS NEPHROPATHY
23rd Malaysian Society of Nephrology Annual Seminar
Johor Bahru, Malaysia
11-13th April 2007
International
ACUTE RENAL FAILURE IN THE SAME HOSPITAL 10 YEARS APART;
A COMPARISON OF TWO PROSPECTIVE STUDIES IN SULTANAH AMINAH
HOSPITAL, JOHOR BAHRU, MALAYSIA
Poster Presentation- 3rd World Congress of Nephrology
Post Congress Satellite Symposium
Acute Renal Failure: From Bench to Bedside
1st -3rd July 2005
LACTIC ACIDOSIS IN HIV PATIENTS RECEIVING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY- THE JOHOR BAHRU EXPERIENCE
Oral Presentation
14th IUSTI Asia Pacific International Conference- 27th to 30th July, 2006
ADULT POLYCYSTIC KIDNEY DISEASE IN PATIENTS ON DIALYSIS IN MALAYSIA
11th Asian Pacific Congress of Nephrology 2008
ELDERLY PATIENTS INITIATING DIALYSIS IN MALAYSIA
11th Asian Pacific Congress of Nephrology 2008
MALIGNANCY POST RENAL TRANSPLANTATION: A 25 YEAR EXPERIENCE
11th Asian Pacific Congress of Nephrology 2008
LATE ACUTE ANTIBODY MEDIATED REJECTION ASSOCIATED WITH CALCINEURIN INHIBITOR MINIMISATION
11th Asian Pacific Congress of Nephrology 2008
CASTLEMAN’S DISEASE OF THE KIDNEY IN PATIENT WITH SLE
11th Asian Pacific Congress of Nephrology 2008
CLINICAL BENEFITS OF ICODEXTRIN: A SINGLE CENTRE EXPERIENCE
11th Asian Pacific Congress of Nephrology 2008
‘SUDOKU’ INCREASES COGNITIVE FUNCTION IN HAEMODIALYSIS PATIENTS- A PROSPECTIVE PILOT STUDY (Awarded Best Abstract)
11th Asian Pacific Congress of Nephrology 2008
SHORT TERM INFECTIOUS COMPLICATIONS POST RENAL TRANSPLANT
11th Asian Pacific Congress of Nephrology 2008
Thursday, December 24, 2009
Wednesday, April 8, 2009
Neuro Behcet's Disease
Types of NBD
NBD is sub-classified into two major forms: parenchymal and non-parenchymal. The two types rarely occur in the same individual and their pathogeneses are probably different (7).
A. Parenchymal NBD
The parenchymal form of NBD is characterized by focal or multifocal involvement of the brain parenchyma. It is the most common presentation reported in NBD (11), comprising 81% of cases in a study of 200 NBD patients (7). This form of NBD commonly presents with an attack of hemiparesis, cognitive changes, sphincteric troubles and possible fever in men in their third decade. The most common clinical findings are pyramidal tract and brain stem signs. An acute attack may be followed by a relapsing or progressive course (2, 7).
MRI findings in parenchymal NBD: MRI is the most sensitive imaging modality for assessing patients with NBD (18); it shows focal or multifocal CNS abnormalities in the clinically affected areas (17, 19, and 20). The distribution and the MRI signal behavior of parenchymal NBD lesions will be reviewed.
Distribution of parenchymal NBD: Lesions in parenchymal NBD are located in the brainstem, thalami and basal ganglia. However, it can also involve the cerebral hemispheres, cerebellum, spinal cord, and other sites.
Brainstem-thalamic-basal ganglia: Parenchymal NBD lesions have predilection to the brainstem-thalamic-basal ganglia region (Fig 1). They characteristically involve the junction of midbrain and thalamus (meso-diencephalic junction) (Fig 2). The reason for this predilection is unknown (10, 21, 22, and 23). Extensive large lesions are commonly seen in these regions during acute attacks (7).
In the brainstem, the midbrain is most commonly affected site (Fig 3), with the cerebral peduncles involved and the red nuclei characteristically spared (17). The next most common location is the ponto-bulbar region (7, 22), with lesions that usually involve the basis pontis (Fig 4) and occasionally extend to brachium pontis (17, 19, 20, and 21). Although the white matter is more often involved in NBD, lesions may also be seen within the grey matter structures, including brainstem nuclei, cortex and basal ganglia (21, 24). Figure 5 shows symmetrical involvement of midbrain colliculi in parenchymal NBD. The disease commonly involves the basal ganglia and internal capsule region unilaterally (Fig 6), or bilaterally in one third of the cases (7). The globus pallidus and adjacent internal capsule is the most common site affected in this region (Fig 7) (10, 22).
High linear signal intensity in T2 weighted images along the posterior limb of the internal capsule is highly suggestive of NBD (Fig 8). This sign can be seen unilaterally or bilaterally with variable symmetry and severity (7, 22, and 23).
Lesions located in the basal ganglia regions tend to extend caudally along the corticospinal tracts (Fig 9). High signal intensity changes may thus be seen in the fiber tracts of the brainstem and may further extend to the cervical cord (Fig 10). The reversibility of signal changes along this pathway in follow-up MR studies is suggestive that they may represent edema (22). However, in chronic NBD cases, non-reversible signal changes in this distribution can be attributed to wallerian degeneration of the tracts documented in pathological studies (16, 24).
Hemispheric lesions: In sub-acute NBD (a few months after an acute attack,: during either remission or progressive worsening of an acute attack), hemispheric lesions may be seen concomitant with brainstem-thalamic-basal ganglia lesions (7). Hemispheric lesions of NBD are usually subcortical rather than periventricular (Fig 11) (25). However, extensive periventricular white matter changes have been reported (Fig 12) (19, 20, and 26).
Other brain lesions:Cerebellar lesions are less common in parenchymal NBD (7). However, lesions in the cerebellar white matters are occasionally encountered in parenchymal NBD (Fig 13) (7, 22). Involvement of the cranial nerves, rootlet of the spinal nerves and peripheral nerves is exceedingly rare. Contrary to the common belief, isolated aseptic meningitis is distinctly uncommon in BD. Instead, diffuse meningoencephalitis is common (22).
Brainstem atrophy:In chronic stage of NBD, gliosis and atrophy may occur (19, 23, and 27) with striking involvement of the brainstem (Fig 14). Isolated atrophy of the brainstem with relative sparing of the cerebral cortex, though not very frequent, is characteristic of chronic NBD (26).
Spinal cord:The spinal cord is less commonly involved in NBD compared to brainstem-thalamic-basal ganglia or hemispheric regions. The spinal cord lesions tend to extend over two or more vertebral segments posterolaterally and may involve the cervico-medullary junction (Fig 15) (22).
MRI signal behavior of parenchymal NBD:The parenchymal lesions of NBD are hyper intense on T2-weighted images. High-signal intensity lesions represent demyelination, gliosis or transient inflammation and secondary edema supported by the resolution of MR abnormalities in response to methyl-prednisolone and other immunosuppressive therapies (28). Most lesions are somewhat visible on T1 weighted images, but can be very subtle (Fig 8) (7, 19, 22, 23, and 27). Hypointense lesions on T1-weighted images may be seen in chronic lesions (Fig 7) (17). Fluid attenuation inversion recovery (FLAIR) sequences increase MRI sensitivity for NBD lesions, especially juxta-cortical and periventricular (Fig 16) (19). Some lesions may demonstrate contrast enhancement during the acute or the sub-acute phase that resolves in remissions (22, 30). The area of contrast uptake can be nodular, linear, crescentic or irregular and is usually smaller than 5 mm (Fig 17) (18, 25). These changes likely reflect a breakdown in the blood-brain barrier (18).
Temporal course of MRI lesions in parenchymal NBD: Acute phase: There are extensive large parenchymal lesions with predominant involvement of the brainstem-thalamic-basal ganglia region that tend to enhance in contrast studies (Fig 1).
Sub-acute phase: There is marked regression in the appearance of the lesions seen during the acute phase, while there may be smaller scattered lesions in the cerebral white matters and brainstem-thalamic-basal ganglia regions (Fig 11).
Chronic phase: There is marked reduction in the size of the parenchymal lesions that corresponds to clinical remissions and possible appearance of brainstem atrophy (Fig 18) (7, 27, and 31).
Pathological findings in parenchymal NBD:Autopsy studies and biopsy specimens of parenchymal NBD reveal widespread meningoencephalitis with multifocal necrotic foci that tend to accumulate mostly in the brainstem and basal ganglion region (23, 24). A non-specific inflammatory reaction with peri-vascular neurtorphilic or lymphocytic cuffing is commonly seen (23, 24). Gliosis and inflammatory axonal injury are reported in chronic lesions (Fig 19) (32, 33).
The precise pathologic mechanism of parenchymal NBD lesions has not been established. It has been hypothesized that parenchymal NBD lesions could be venous infarcts (22). This hypothesis needs more pathological support as vasculitis cannot usually be demonstrated within the parenchymal NBD lesions (17, 31-33). The presence of abnormal T-cell lymphocyte function points to a possible aberrant immune response to antigenic components of infectious agents such as Streptococcus species (6, 32 and 33).
B. Non-parenchymal NBD:
In the non-parenchymal group, CNS dysfunction is due to involvement of major vessels (vascular NBD) or rarely aseptic meningitis (7). The vascular form of NBD is more often reported from the Middle East (14, 34) and France (35), and less often from other parts of the world (7, 17) with geographical and ethnic variations in disease expression and severity (36).
Vascular NBD usually affects major intracranial vessels with frequent involvement of the venous sinuses, cerebral veins and less commonly the intracranial arteries (7, 35, 37-39). The rare arterial involvements in NBD include thrombosis and aneurysms of the large cerebral arteries (37, 38). Venous sinus thrombosis is the most frequent vascular manifestation in NBD (35, 40) followed by thrombosed deep and cortical cerebral veins (41). The association of venous parenchymal infarcts with venous thrombosis depends on the efficacy of the collateral circulation within the cerebral venous system. The extensive collateral circulation usually allows for a significant degree of compensation in the early stages of sinus venous thrombosis (42).
Vascular NBD usually manifests with acute neurological attacks. The arterial involvement usually presents with stroke that evolves over several hours (7). Raised intracranial pressure is the main clinical manifestation of venous sinus thrombosis with a spectrum of clinical presentations such as headaches, papilloedema, focal neurological deficits, seizures and coma. However, the clinical diagnosis of acute dural sinus occlusion can be difficult to make and is frequently delayed (42).
MRI findings in vascular NBD: The most common MRI findings in vascular NBD are occlusion of the cerebral venous sinuses without or with venous infarcts (7). MRI in conjunction with MR venography (MRV) is highly sensitive in detecting such lesions (42-44).
Venous sinus thrombosis: MRI findings include:
Direct visualization of a thrombus within the vessel. The increased intensity thrombus, detected on T1- and T2- weighted images, may partially or totally replace the flow void of the normal venous channel (Fig 20) (42).
MR venography (MRV) shows lack or impaired flow in the occluded sinus and identifies venous collaterals (Fig 21) (45, 46).
Venous infarcts: Venous infarcts are characterized by their non-arterial distribution. They involve the white matter and/or the cortical-white matter junction, and are often associated with hemorrhage. Bilateral cerebral involvement can occur, including the superior cerebral white matter of the convexities from superior sagittal sinus thrombosis (Fig 22) or the basal ganglia and thalami from internal cerebral vein thrombosis (41, 42).
Parenchymal versus non-parenchymal NBD:
Differentiating between parenchymal and non-parenchymal NBD has significant diagnostic, pathologic, therapeutic, and prognostic implications. Vascular NBD due to isolated intracranial hypertension and dural venous sinus thrombosis have better prognosis if detected and treated early. Acute lesions of parenchymal NBD can be reversible with appropriate treatment such as corticosteroids (11).
The most common forms of NBD, parenchymal and vascular, are distinguished by their unique clinical presentations, characteristic changes in the cerebrospinal fluid (CSF), and MRI findings. Clinically, the parenchymal form manifests with signs and symptoms referable to the brainstem with pyramidal findings, cognitive impairment, ataxia and sphincter disturbance; while the vascular form usually causes raised intracranial pressure due to occlusion of the dural sinuses or very rarely an arterial stroke. CSF findings are different in both groups. In parenchymal NBD, CSF shows pleocytosis with predominance of polymorphonuclear cells, with or without elevated protein level and rarely positive oligoclonal bands. In vascular NBD, the CSF is usually normal except for elevated pressure (22). Conventional MRI can usually differentiate between parenchymal and vascular NBD. However, in some cases, the differentiation between vascular and parenchymal NBD may be difficult because of the presence of parenchymal lesions in the former or in rare instances the coexistence of the two forms. In such cases, special sequences of MRI, such as diffusion-weighted imaging (DWI) or magnetic resonance spectroscopy (MRS), can provide additional information.
NBD is sub-classified into two major forms: parenchymal and non-parenchymal. The two types rarely occur in the same individual and their pathogeneses are probably different (7).
A. Parenchymal NBD
The parenchymal form of NBD is characterized by focal or multifocal involvement of the brain parenchyma. It is the most common presentation reported in NBD (11), comprising 81% of cases in a study of 200 NBD patients (7). This form of NBD commonly presents with an attack of hemiparesis, cognitive changes, sphincteric troubles and possible fever in men in their third decade. The most common clinical findings are pyramidal tract and brain stem signs. An acute attack may be followed by a relapsing or progressive course (2, 7).
MRI findings in parenchymal NBD: MRI is the most sensitive imaging modality for assessing patients with NBD (18); it shows focal or multifocal CNS abnormalities in the clinically affected areas (17, 19, and 20). The distribution and the MRI signal behavior of parenchymal NBD lesions will be reviewed.
Distribution of parenchymal NBD: Lesions in parenchymal NBD are located in the brainstem, thalami and basal ganglia. However, it can also involve the cerebral hemispheres, cerebellum, spinal cord, and other sites.
Brainstem-thalamic-basal ganglia: Parenchymal NBD lesions have predilection to the brainstem-thalamic-basal ganglia region (Fig 1). They characteristically involve the junction of midbrain and thalamus (meso-diencephalic junction) (Fig 2). The reason for this predilection is unknown (10, 21, 22, and 23). Extensive large lesions are commonly seen in these regions during acute attacks (7).
In the brainstem, the midbrain is most commonly affected site (Fig 3), with the cerebral peduncles involved and the red nuclei characteristically spared (17). The next most common location is the ponto-bulbar region (7, 22), with lesions that usually involve the basis pontis (Fig 4) and occasionally extend to brachium pontis (17, 19, 20, and 21). Although the white matter is more often involved in NBD, lesions may also be seen within the grey matter structures, including brainstem nuclei, cortex and basal ganglia (21, 24). Figure 5 shows symmetrical involvement of midbrain colliculi in parenchymal NBD. The disease commonly involves the basal ganglia and internal capsule region unilaterally (Fig 6), or bilaterally in one third of the cases (7). The globus pallidus and adjacent internal capsule is the most common site affected in this region (Fig 7) (10, 22).
High linear signal intensity in T2 weighted images along the posterior limb of the internal capsule is highly suggestive of NBD (Fig 8). This sign can be seen unilaterally or bilaterally with variable symmetry and severity (7, 22, and 23).
Lesions located in the basal ganglia regions tend to extend caudally along the corticospinal tracts (Fig 9). High signal intensity changes may thus be seen in the fiber tracts of the brainstem and may further extend to the cervical cord (Fig 10). The reversibility of signal changes along this pathway in follow-up MR studies is suggestive that they may represent edema (22). However, in chronic NBD cases, non-reversible signal changes in this distribution can be attributed to wallerian degeneration of the tracts documented in pathological studies (16, 24).
Hemispheric lesions: In sub-acute NBD (a few months after an acute attack,: during either remission or progressive worsening of an acute attack), hemispheric lesions may be seen concomitant with brainstem-thalamic-basal ganglia lesions (7). Hemispheric lesions of NBD are usually subcortical rather than periventricular (Fig 11) (25). However, extensive periventricular white matter changes have been reported (Fig 12) (19, 20, and 26).
Other brain lesions:Cerebellar lesions are less common in parenchymal NBD (7). However, lesions in the cerebellar white matters are occasionally encountered in parenchymal NBD (Fig 13) (7, 22). Involvement of the cranial nerves, rootlet of the spinal nerves and peripheral nerves is exceedingly rare. Contrary to the common belief, isolated aseptic meningitis is distinctly uncommon in BD. Instead, diffuse meningoencephalitis is common (22).
Brainstem atrophy:In chronic stage of NBD, gliosis and atrophy may occur (19, 23, and 27) with striking involvement of the brainstem (Fig 14). Isolated atrophy of the brainstem with relative sparing of the cerebral cortex, though not very frequent, is characteristic of chronic NBD (26).
Spinal cord:The spinal cord is less commonly involved in NBD compared to brainstem-thalamic-basal ganglia or hemispheric regions. The spinal cord lesions tend to extend over two or more vertebral segments posterolaterally and may involve the cervico-medullary junction (Fig 15) (22).
MRI signal behavior of parenchymal NBD:The parenchymal lesions of NBD are hyper intense on T2-weighted images. High-signal intensity lesions represent demyelination, gliosis or transient inflammation and secondary edema supported by the resolution of MR abnormalities in response to methyl-prednisolone and other immunosuppressive therapies (28). Most lesions are somewhat visible on T1 weighted images, but can be very subtle (Fig 8) (7, 19, 22, 23, and 27). Hypointense lesions on T1-weighted images may be seen in chronic lesions (Fig 7) (17). Fluid attenuation inversion recovery (FLAIR) sequences increase MRI sensitivity for NBD lesions, especially juxta-cortical and periventricular (Fig 16) (19). Some lesions may demonstrate contrast enhancement during the acute or the sub-acute phase that resolves in remissions (22, 30). The area of contrast uptake can be nodular, linear, crescentic or irregular and is usually smaller than 5 mm (Fig 17) (18, 25). These changes likely reflect a breakdown in the blood-brain barrier (18).
Temporal course of MRI lesions in parenchymal NBD: Acute phase: There are extensive large parenchymal lesions with predominant involvement of the brainstem-thalamic-basal ganglia region that tend to enhance in contrast studies (Fig 1).
Sub-acute phase: There is marked regression in the appearance of the lesions seen during the acute phase, while there may be smaller scattered lesions in the cerebral white matters and brainstem-thalamic-basal ganglia regions (Fig 11).
Chronic phase: There is marked reduction in the size of the parenchymal lesions that corresponds to clinical remissions and possible appearance of brainstem atrophy (Fig 18) (7, 27, and 31).
Pathological findings in parenchymal NBD:Autopsy studies and biopsy specimens of parenchymal NBD reveal widespread meningoencephalitis with multifocal necrotic foci that tend to accumulate mostly in the brainstem and basal ganglion region (23, 24). A non-specific inflammatory reaction with peri-vascular neurtorphilic or lymphocytic cuffing is commonly seen (23, 24). Gliosis and inflammatory axonal injury are reported in chronic lesions (Fig 19) (32, 33).
The precise pathologic mechanism of parenchymal NBD lesions has not been established. It has been hypothesized that parenchymal NBD lesions could be venous infarcts (22). This hypothesis needs more pathological support as vasculitis cannot usually be demonstrated within the parenchymal NBD lesions (17, 31-33). The presence of abnormal T-cell lymphocyte function points to a possible aberrant immune response to antigenic components of infectious agents such as Streptococcus species (6, 32 and 33).
B. Non-parenchymal NBD:
In the non-parenchymal group, CNS dysfunction is due to involvement of major vessels (vascular NBD) or rarely aseptic meningitis (7). The vascular form of NBD is more often reported from the Middle East (14, 34) and France (35), and less often from other parts of the world (7, 17) with geographical and ethnic variations in disease expression and severity (36).
Vascular NBD usually affects major intracranial vessels with frequent involvement of the venous sinuses, cerebral veins and less commonly the intracranial arteries (7, 35, 37-39). The rare arterial involvements in NBD include thrombosis and aneurysms of the large cerebral arteries (37, 38). Venous sinus thrombosis is the most frequent vascular manifestation in NBD (35, 40) followed by thrombosed deep and cortical cerebral veins (41). The association of venous parenchymal infarcts with venous thrombosis depends on the efficacy of the collateral circulation within the cerebral venous system. The extensive collateral circulation usually allows for a significant degree of compensation in the early stages of sinus venous thrombosis (42).
Vascular NBD usually manifests with acute neurological attacks. The arterial involvement usually presents with stroke that evolves over several hours (7). Raised intracranial pressure is the main clinical manifestation of venous sinus thrombosis with a spectrum of clinical presentations such as headaches, papilloedema, focal neurological deficits, seizures and coma. However, the clinical diagnosis of acute dural sinus occlusion can be difficult to make and is frequently delayed (42).
MRI findings in vascular NBD: The most common MRI findings in vascular NBD are occlusion of the cerebral venous sinuses without or with venous infarcts (7). MRI in conjunction with MR venography (MRV) is highly sensitive in detecting such lesions (42-44).
Venous sinus thrombosis: MRI findings include:
Direct visualization of a thrombus within the vessel. The increased intensity thrombus, detected on T1- and T2- weighted images, may partially or totally replace the flow void of the normal venous channel (Fig 20) (42).
MR venography (MRV) shows lack or impaired flow in the occluded sinus and identifies venous collaterals (Fig 21) (45, 46).
Venous infarcts: Venous infarcts are characterized by their non-arterial distribution. They involve the white matter and/or the cortical-white matter junction, and are often associated with hemorrhage. Bilateral cerebral involvement can occur, including the superior cerebral white matter of the convexities from superior sagittal sinus thrombosis (Fig 22) or the basal ganglia and thalami from internal cerebral vein thrombosis (41, 42).
Parenchymal versus non-parenchymal NBD:
Differentiating between parenchymal and non-parenchymal NBD has significant diagnostic, pathologic, therapeutic, and prognostic implications. Vascular NBD due to isolated intracranial hypertension and dural venous sinus thrombosis have better prognosis if detected and treated early. Acute lesions of parenchymal NBD can be reversible with appropriate treatment such as corticosteroids (11).
The most common forms of NBD, parenchymal and vascular, are distinguished by their unique clinical presentations, characteristic changes in the cerebrospinal fluid (CSF), and MRI findings. Clinically, the parenchymal form manifests with signs and symptoms referable to the brainstem with pyramidal findings, cognitive impairment, ataxia and sphincter disturbance; while the vascular form usually causes raised intracranial pressure due to occlusion of the dural sinuses or very rarely an arterial stroke. CSF findings are different in both groups. In parenchymal NBD, CSF shows pleocytosis with predominance of polymorphonuclear cells, with or without elevated protein level and rarely positive oligoclonal bands. In vascular NBD, the CSF is usually normal except for elevated pressure (22). Conventional MRI can usually differentiate between parenchymal and vascular NBD. However, in some cases, the differentiation between vascular and parenchymal NBD may be difficult because of the presence of parenchymal lesions in the former or in rare instances the coexistence of the two forms. In such cases, special sequences of MRI, such as diffusion-weighted imaging (DWI) or magnetic resonance spectroscopy (MRS), can provide additional information.
Sunday, April 5, 2009
Thursday, February 26, 2009
EULAR recommendations- vasculitis (Medium and small vessel vasculitis)
Medium and small vessel vasculitis- Wegener’s, Microscopic polyangiitis, Churg-strauss, PAN, Cryoglobulinaemia.
1. Management is to be in expert centres
• Its rarity makes management in normal settings suboptimal
• Specialised services may be required
2. ANCA must be done (both indirect IF and ELISA)
3. Positive biopsy in strongly supportive of vasculitis
• Fibrinoid necrosis
• Pauci-immune GN (segmental necrosis, extracapillary proliferation)
• Granuloma
• Biopsy esp helpful in ANCA negative pt
4. Clinic visits- structured assessment is required (ie checklist- clinical, urine, laboratory)
• To avoid missing the multi-organ involvement
5. Treatment is based on severity
• Localised
• Early systemic (any, without organ threatening or life threatening disease)
• Generalized (renal or other vital organ failure, serum creat >500umol/l)
• Severe (renal or other vital organ failure, serum creat >500umol/l)
• Refractory (unresponsive to steroids/cyclophos)
6. WG/MPA
• Induction:- Cyclophosphamide (oral 2mg/kg/d max 200mg/d) and prednisolone (1mg/kg/d max 60mg/d)
• Pulse IV Cyclophos- higher remission rate with lower A/E but higher rate of relapse
1. EUVAS regime- 15mg/kg (max 1.2g) 2 weekly IV cyclophosphamide for 3 pulses, then 3 weekly for 3-6 pulses. (dose adjusted for age and renal function)
7. PAN/CSS
• Induction:- Cyclophosphamide + steroids- better remission vs steroid alone.
• IV versus oral cyclophosphamide
• Lower A/E and equal efficacy in PAN pt
8. Cyclophosphamide therapy
• Mesna
• PCP prophylaxis (480mg dly or 960mg 3 times a week)
9. Non organ threatening or non life threatening ANCA associated vasculitis
• MTX (oral/IV) and steroids- acceptable less toxic alternative
10. Plasma exchange in pt with RPGN (with serum creatinine > 500umol/l)
11. Maintenance therapy- Steroids + Azathioprine, lefllunomide or MTX
12. Patients who failed remission or relapse despite on maximum doses of standard therapy –
• MMF
• Anti TNF (infliximab)
• RTX
• IVIG
• ATG
13. Cryoglobulinemia
• Mixed essential- treat as small vessel vasculitis
• RTX in hepatitis associated cryoglobulinemic vasculitis may be of benefit
14. HepC associated cryoglobulinaemic vasculitis- anti viral therapy
15. HepB associated PAN- antiviral therapy + steroids + plasma exchange
1. Management is to be in expert centres
• Its rarity makes management in normal settings suboptimal
• Specialised services may be required
2. ANCA must be done (both indirect IF and ELISA)
3. Positive biopsy in strongly supportive of vasculitis
• Fibrinoid necrosis
• Pauci-immune GN (segmental necrosis, extracapillary proliferation)
• Granuloma
• Biopsy esp helpful in ANCA negative pt
4. Clinic visits- structured assessment is required (ie checklist- clinical, urine, laboratory)
• To avoid missing the multi-organ involvement
5. Treatment is based on severity
• Localised
• Early systemic (any, without organ threatening or life threatening disease)
• Generalized (renal or other vital organ failure, serum creat >500umol/l)
• Severe (renal or other vital organ failure, serum creat >500umol/l)
• Refractory (unresponsive to steroids/cyclophos)
6. WG/MPA
• Induction:- Cyclophosphamide (oral 2mg/kg/d max 200mg/d) and prednisolone (1mg/kg/d max 60mg/d)
• Pulse IV Cyclophos- higher remission rate with lower A/E but higher rate of relapse
1. EUVAS regime- 15mg/kg (max 1.2g) 2 weekly IV cyclophosphamide for 3 pulses, then 3 weekly for 3-6 pulses. (dose adjusted for age and renal function)
7. PAN/CSS
• Induction:- Cyclophosphamide + steroids- better remission vs steroid alone.
• IV versus oral cyclophosphamide
• Lower A/E and equal efficacy in PAN pt
8. Cyclophosphamide therapy
• Mesna
• PCP prophylaxis (480mg dly or 960mg 3 times a week)
9. Non organ threatening or non life threatening ANCA associated vasculitis
• MTX (oral/IV) and steroids- acceptable less toxic alternative
10. Plasma exchange in pt with RPGN (with serum creatinine > 500umol/l)
11. Maintenance therapy- Steroids + Azathioprine, lefllunomide or MTX
12. Patients who failed remission or relapse despite on maximum doses of standard therapy –
• MMF
• Anti TNF (infliximab)
• RTX
• IVIG
• ATG
13. Cryoglobulinemia
• Mixed essential- treat as small vessel vasculitis
• RTX in hepatitis associated cryoglobulinemic vasculitis may be of benefit
14. HepC associated cryoglobulinaemic vasculitis- anti viral therapy
15. HepB associated PAN- antiviral therapy + steroids + plasma exchange
EULAR recommendations: Vasculitis (Large vessel vasculitis)
Large vessel vasculitis (LVV)- Takayasu and GCA:-
1. Thorough clinical and imaging assessment of the arterial tree when a diagnosis of Takayasu is suspected-
• MRA/PET could assist in diagnosis and document of extent of involvement but has its limitations (not widely available, operator dependant).
• Conventional angiogram is gold standard
2. In Giant cell arteritis,
• Temporal artery biopsy should be performed
• 1cm tissue length is required
• skip lesions may lead to false negative HPE
• Don’t delay treatment while waiting for biopsy. Treat first.
• If CRP/ESR is not elevated, think of another diagnosis
• USG of the temporal artery looking for vessel wall oedema was 88% sensitive and 97% specific in diagnosing GCA
3. Start steroids early and at high dose for induction of remission of LVV
• Prednisolone- 1mg/kg (max 60mg) daily
• Maintain for 1 month then taper
• Taper should not be in the form of EOD therapy which is a/w higher relapse rate
• At 3 months, steroid dose should be at 10-15mg/d
• Steroid duration could be for several years
• Must give bone protection during this period
4. Immunosuppressive agents should be considered in LVV as adjunctive therapy
• Methotrexate (20-25mg weekly)
• Azathioprine (2mg/kg/d)
• Cyclophosphamide (in steroid resistant Takayasu)
5. Monitoring of LVV- clinical and inflammatory markers
6. Use low dose aspirin in all GCA pt
7. Reconstructive surgery for Takayasu should be performed during the quiescent phase at expert centres
1. Thorough clinical and imaging assessment of the arterial tree when a diagnosis of Takayasu is suspected-
• MRA/PET could assist in diagnosis and document of extent of involvement but has its limitations (not widely available, operator dependant).
• Conventional angiogram is gold standard
2. In Giant cell arteritis,
• Temporal artery biopsy should be performed
• 1cm tissue length is required
• skip lesions may lead to false negative HPE
• Don’t delay treatment while waiting for biopsy. Treat first.
• If CRP/ESR is not elevated, think of another diagnosis
• USG of the temporal artery looking for vessel wall oedema was 88% sensitive and 97% specific in diagnosing GCA
3. Start steroids early and at high dose for induction of remission of LVV
• Prednisolone- 1mg/kg (max 60mg) daily
• Maintain for 1 month then taper
• Taper should not be in the form of EOD therapy which is a/w higher relapse rate
• At 3 months, steroid dose should be at 10-15mg/d
• Steroid duration could be for several years
• Must give bone protection during this period
4. Immunosuppressive agents should be considered in LVV as adjunctive therapy
• Methotrexate (20-25mg weekly)
• Azathioprine (2mg/kg/d)
• Cyclophosphamide (in steroid resistant Takayasu)
5. Monitoring of LVV- clinical and inflammatory markers
6. Use low dose aspirin in all GCA pt
7. Reconstructive surgery for Takayasu should be performed during the quiescent phase at expert centres
Monday, February 9, 2009
Equivalent anti-inflammatory doses of different oral corticosteroids
This table takes no account of mineralocorticoid effects, nor does it take account of variations in duration of action
Prednisolone 5mg
is equivalent to betamethasone 750 mcg
is equivalent to cortisone acetate 25 mg
is equivalent to dexamethasone 750 mcg
is equivalent to deflazacort 6mg
is equivalent to hydrocortisone 20mg
is equivalent to methylprednisolone 4mg
is equivalent to traimacinolone 4mg
Prednisolone 5mg
is equivalent to betamethasone 750 mcg
is equivalent to cortisone acetate 25 mg
is equivalent to dexamethasone 750 mcg
is equivalent to deflazacort 6mg
is equivalent to hydrocortisone 20mg
is equivalent to methylprednisolone 4mg
is equivalent to traimacinolone 4mg
Wednesday, January 21, 2009
Journal Club- 21/1/2009 CIMR
The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance
Alejandro Villagra1, Fengdong Cheng1, Hong-Wei Wang1, Ildelfonso Suarez1,2, Michelle Glozak3,4, Michelle Maurin1, Danny Nguyen1, Kenneth L Wright1,4, Peter W Atadja5, Kapil Bhalla6, Javier Pinilla-Ibarz1,4, Edward Seto3,4 & Eduardo M Sotomayor1,3,4
Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical ‘decision’ is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical ‘decision’ with substantial implications in autoimmunity, transplantation and cancer immunotherapy.
Alejandro Villagra1, Fengdong Cheng1, Hong-Wei Wang1, Ildelfonso Suarez1,2, Michelle Glozak3,4, Michelle Maurin1, Danny Nguyen1, Kenneth L Wright1,4, Peter W Atadja5, Kapil Bhalla6, Javier Pinilla-Ibarz1,4, Edward Seto3,4 & Eduardo M Sotomayor1,3,4
Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical ‘decision’ is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical ‘decision’ with substantial implications in autoimmunity, transplantation and cancer immunotherapy.
Thursday, January 15, 2009
Humoral Immunity
Slides have been intentionally made 'wordy' to enable better understanding of the topic.
Wednesday, January 14, 2009
Journal Club- 14th January 2009 (CIMR)
Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
Maria Florencia Delgado1, Silvina Coviello1, A Clara Monsalvo1, Guillermina A Melendi1,2, Johanna Zea Hernandez1,2, Juan P Batalle1, Leandro Diaz1, Alfonsina Trento3, Herng-Yu Chang4, Wayne Mitzner4, Jeffrey Ravetch5, Jose ́ A Melero3, Pablo M Irusta1,6 & Fernando P Polack1,2,7,8
Abstract:
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
Maria Florencia Delgado1, Silvina Coviello1, A Clara Monsalvo1, Guillermina A Melendi1,2, Johanna Zea Hernandez1,2, Juan P Batalle1, Leandro Diaz1, Alfonsina Trento3, Herng-Yu Chang4, Wayne Mitzner4, Jeffrey Ravetch5, Jose ́ A Melero3, Pablo M Irusta1,6 & Fernando P Polack1,2,7,8
Abstract:
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
Monday, January 12, 2009
Thursday, January 8, 2009
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