MyMedR

Fulltext Pathology of acute henipavirus infection in humans and animals

Wong KT, Ong KC

Patholog Res Int, 2011;2011:567248.

PMID: 21961078 DOI: 10.4061/2011/567248

Zoonoses as causes of human infections have been increasingly reported, and many of these are viruses that cause central nervous system infections. This paper focuses on the henipaviruses (family Paramyxoviridae, genus henipavirus) that have recently emerged to cause severe encephalitis and systemic infection in humans and animals in the Asia-Pacific region. The pathological features in the human infections comprise vasculopathy (vasculitis, endothelial multinucleated syncytia, thrombosis, etc.) and parenchymal cell infection in the central nervous system, lung, kidney, and other major organs. Most animals naturally or experimentally infected show more or less similar features confirming the dual pathogenetic mechanism of vasculopathy-associated microinfarction and direct extravascular parenchymal cell infection as causes of tissue injury. The most promising animal models include the hamster, ferret, squirrel monkey, and African green monkey. With increasing evidence of infection in the natural hosts, the pteropid bats and, hence, probable future outbreaks in many more countries, a greater awareness of henipavirus infection in both humans and animals is imperative.

Fulltext Acute respiratory failure in melioidosis

Puthucheary SD, Vadivelu J, Wong KT, Ong GS

Singapore Med J, 2001 Mar;42(3):117-21.

PMID: 11405563

In melioidosis caused by Burkholderia pseudomallei, although every organ in the body may be involved, the highest mortality of 73% occurs when the respiratory system is affected. These patients invariably die of acute respiratory failure. Most of them also have underlying predisposing factors like diabetes mellitus.

Oculopharyngeal muscular dystrophy with PABPN1 mutation in a Chinese Malaysian woman

Goh KJ, Wong KT, Nishino I, Minami N, Nonaka I

Neuromuscul Disord, 2005 Mar;15(3):262-4.

PMID: 15725589

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder of middle age presenting as progressive dysphagia and eyelid ptosis, due to short expansions of the GCG trinucleotide repeat (from GCG6 to GCG8-13) in the polyadenylate binding-protein nuclear 1 (PABPN1) gene. OPMD is rarely seen in Asians and morphologically and/or genetically confirmed cases have been reported in Japanese kindreds only. We report a 64 year old Chinese-Malaysian woman who presented with progressive dysphagia and bilateral ptosis for about 6 years. Her mother and elder brother (both deceased) were believed to be affected. Muscle histopathology revealed angulated fibres with rimmed vacuoles. Genetic analysis showed repeat expansion in one allele to (GCG)9 while normal in the other (GCG)6. This is the first non-Japanese Asian family with genetically confirmed OPMD.

Fulltext Clinical practice with steroid therapy for Duchenne muscular dystrophy: An expert survey in Asia and Oceania

Takeuchi F, Nakamura H, Yonemoto N, Komaki H, Rosales RL, Kornberg AJ, et al.

Brain Dev, 2020 Mar;42(3):277-288.

PMID: 31980267 DOI: 10.1016/j.braindev.2019.12.005

BACKGROUND: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network.

RESULTS: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed.

CONCLUSIONS: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary.

Absence of beta-amyloid deposition in the central nervous system of a transgenic mouse model of distal myopathy with rimmed vacuoles

Anada RP, Wong KT, Malicdan MC, Goh KJ, Hayashi Y, Nishino I, et al.

Amyloid, 2014 Jun;21(2):138-9.

PMID: 24601867 DOI: 10.3109/13506129.2014.889675

Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis

Wong KT, Shieh WJ, Kumar S, Norain K, Abdullah W, Guarner J, et al.

Am J Pathol, 2002 Dec;161(6):2153-67.

PMID: 12466131

In 1998, an outbreak of acute encephalitis with high mortality rates among pig handlers in Malaysia led to the discovery of a novel paramyxovirus named Nipah virus. A multidisciplinary investigation that included epidemiology, microbiology, molecular biology, and pathology was pivotal in the discovery of this new human infection. Clinical and autopsy findings were derived from a series of 32 fatal human cases of Nipah virus infection. Diagnosis was established in all cases by a combination of immunohistochemistry (IHC) and serology. Routine histological stains, IHC, and electron microscopy were used to examine autopsy tissues. The main histopathological findings included a systemic vasculitis with extensive thrombosis and parenchymal necrosis, particularly in the central nervous system. Endothelial cell damage, necrosis, and syncytial giant cell formation were seen in affected vessels. Characteristic viral inclusions were seen by light and electron microscopy. IHC analysis showed widespread presence of Nipah virus antigens in endothelial and smooth muscle cells of blood vessels. Abundant viral antigens were also seen in various parenchymal cells, particularly in neurons. Infection of endothelial cells and neurons as well as vasculitis and thrombosis seem to be critical to the pathogenesis of this new human disease.

Fulltext Alleged paraquat poisoning in Perak

Wong KT, Ng TS

Med J Malaysia, 1984 Mar;39(1):52-5.

PMID: 6334801

This communication describes a survey on 94 cases of alleged paraquat poisoning for a period of one-and a-half years in Perak state. The highest prevalence of such cases was noted in the district of Batang Padang. The incidences between males and females as well as between married and single persons were found to be equal, 81.9% were Indians and 73.4% were suicidal cases. More than 80% of the cases were in the 10-to-40-years age group.

Fulltext Paraquat poisoning

Wong KT, Ng TS

Family Practitioner, 1982;5(3):35-36.

Fulltext R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL

Lim KS, Tan AH, Lim CS, Chua KH, Lee PC, Ramli N, et al.

PLoS One, 2015;10(8):e0135470.

PMID: 26270344 DOI: 10.1371/journal.pone.0135470

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.

Fulltext The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways

Wong KT, Munisamy B, Ong KC, Kojima H, Noriyo N, Chua KB, et al.

J. Neuropathol. Exp. Neurol., 2008 Feb;67(2):162-9.

PMID: 18219253 DOI: 10.1097/nen.0b013e318163a990

Previous neuropathologic studies of Enterovirus 71 encephalomyelitis have not investigated the anatomic distribution of inflammation and viral localization in the central nervous system (CNS) in detail. We analyzed CNS and non-CNS tissues from 7 autopsy cases from Malaysia and found CNS inflammation patterns to be distinct and stereotyped. Inflammation was most marked in spinal cord gray matter, brainstem, hypothalamus, and subthalamic and dentate nuclei; it was focal in the cerebrum, mainly in the motor cortex, and was rare in dorsal root ganglia. Inflammation was absent in the cerebellar cortex, thalamus, basal ganglia, peripheral nerves, and autonomic ganglia. The parenchymal inflammatory response consisted of perivascular cuffs, variable edema, neuronophagia, and microglial nodules. Inflammatory cells were predominantly CD68-positive macrophage/microglia, but there were a few CD8-positive lymphocytes. There were no viral inclusions; viral antigens and RNA were localized only in the somata and processes of small numbers of neurons and in phagocytic cells. There was no evidence of virus in other CNS cells, peripheral nerves, dorsal root autonomic ganglia, or non-CNS organs. The results indicate that Enterovirus 71 is neuronotropic, and that, although hematogenous spread cannot be excluded, viral spread into the CNS could be via neural pathways, likely the motor but not peripheral sensory or autonomic pathways. Viral spread within the CNS seems to involve motor and possibly other pathways.

Fulltext Intramolecular Dimerization Quenching of Delayed Emission in Asymmetric D-D'-A TADF Emitters

Woon KL, Yi CL, Pan KC, Etherington MK, Wu CC, Wong KT, et al.

J Phys Chem C Nanomater Interfaces, 2019 May 16;123(19):12400-12410.

PMID: 32952765 DOI: 10.1021/acs.jpcc.9b01900

Understanding the excited-state dynamics and conformational relaxation in thermally activated delayed fluorescence (TADF) molecules, including conformations that potentially support intramolecular through-space charge transfer, can open new avenues for TADF molecular design as well as elucidate complex photophysical pathways in structurally complex molecules. Emissive molecules comprising a donor (triphenylamine, TPA) and an acceptor (triphenyltriazine, TRZ) bridged by a second donor (9,9-dimethyl-9-10-dihydroacridin, DMAC, or phenoxazine, PXZ) are synthesized and characterized. In solution, the flexibility of the sp3-hybridized carbon atom in DMAC of DMAC-TPA-TRZ, compared to the rigid PXZ, allows significant conformational reorganization, giving rise to multiple charge-transfer excited states. As a result of such a reorganization, the TRZ and TPA moieties become cofacially aligned, driven by a strong dipole-dipole attraction between the TPA and TRZ units, forming a weakly charge-transfer dimer state, in stark contrast to the case of PXZ-TPA-TRZ where the rigid PXZ bridge only supports a single PXZ-TRZ charge transfer (CT) state. The low-energy TPA-TRZ dimer is found to have a high-energy dimer local triplet state, which quenches delayed emission because the resultant singlet CT local triplet energy gap is too large to mediate efficient reverse intersystem crossing. However, organic light-emitting diodes using PXZ-TPA-TRZ as an emitting dopant resulted in external quantum efficiency as high as 22%, more than two times higher than that of DMAC-TPA-TRZ-based device, showing the impact that such intramolecular reorganization and donor-acceptor dimerization have on TADF performance.

Fulltext HIV-Associated CD8 Encephalitis: A UK Case Series and Review of Histopathologically Confirmed Cases

Lucas SB, Wong KT, Nightingale S, Miller RF

Front Neurol, 2021;12:628296.

PMID: 33868143 DOI: 10.3389/fneur.2021.628296

HIV-associated CD8-encephalitis (HIV-CD8E) is a severe inflammatory disorder dominated by infiltration of the brain by CD8+ T-lymphocytes. It occurs in people with HIV, typically when the virus is apparently well-controlled by antiretroviral treatment (ART). HIV-CD8E presents with symptoms and signs related to marked cerebral inflammation and swelling, and can lead to coma and death unless treated promptly with corticosteroids. Risk events such as intercurrent infection, antiretroviral therapy interruption, immune reconstitution inflammatory syndrome (IRIS) after starting ART, and concomitant associations such as cerebrospinal fluid (CSF) HIV viral escape have been identified, but the pathogenesis of the disorder is not known. We present the largest case series of HIV-CD8E to date (n = 23), representing histopathologically confirmed cases in the UK. We also summarize the global literature representing all previously published cases with histopathological confirmation (n = 30). A new variant of HIV-CD8E is described, occurring on a background of HIV encephalitis (HIVE).Together these series, totalling 53 patients, provide new insights. CSF HIV viral escape was a frequent finding in HIV-CD8E occurring in 68% of those with CSF available and tested; ART interruption and IRIS were important, both occurring in 27%. Black ethnicity appeared to be a key risk factor; all but two UK cases were African, as were the majority of the previously published cases in which ethnicity was stated. We discuss potential pathogenic mechanisms, but there is no unifying explanation over all the HIV-CD8E scenarios.

Anisakiasis causing acute dysentery in Malaysia

Amir A, Ngui R, Ismail WH, Wong KT, Ong JS, Lim YA, et al.

Am J Trop Med Hyg, 2016 Aug 03;95(2):410-2.

PMID: 27325803 DOI: 10.4269/ajtmh.16-0007

Human anisakiasis is a zoonosis acquired by eating raw or undercooked infected seafood. Herein, we report a case of acute dysentery caused by anisakiasis in a 64-year-old man in Malaysia. A colonoscopy was performed and a nematode larva was found penetrating the mucosa of the ascending colon. Bleeding was observed at the site of penetration. Y-shaped lateral epidermal cords were seen from the cross section of the worm, which is a prominent feature of Anisakis larva. Molecular analysis using polymerase chain reaction of cytochrome oxidase 2 (cox2) gene confirmed the specimen to be larva of Anisakis simplex.

Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis

He Y, Ong KC, Gao Z, Zhao X, Anderson VM, McNutt MA, et al.

Am J Pathol, 2014 Mar;184(3):714-20.

PMID: 24378407 DOI: 10.1016/j.ajpath.2013.11.009

Enterovirus 71 (EV71; family Picornaviridae, species human Enterovirus A) usually causes hand, foot, and mouth disease, which may rarely be complicated by fatal encephalomyelitis. We investigated extra-central nervous system (extra-CNS) tissues capable of supporting EV71 infection and replication, and have correlated tissue infection with expression of putative viral entry receptors, scavenger receptor B2 (SCARB2), and P-selectin glycoprotein ligand-1 (PSGL-1). Formalin-fixed, paraffin-embedded CNS and extra-CNS tissues from seven autopsy cases were examined by IHC and in situ hybridization to evaluate viral antigens and RNA. Viral receptors were identified with IHC. In all seven cases, the CNS showed stereotypical distribution of inflammation and neuronal localization of viral antigens and RNA, confirming the clinical diagnosis of EV71 encephalomyelitis. In six cases in which tonsillar tissues were available, viral antigens and/or RNA were localized to squamous epithelium lining the tonsillar crypts. Tissues from the gastrointestinal tract, pancreas, mesenteric nodes, spleen, and skin were all negative for viral antigens/RNA. Our novel findings strongly suggest that tonsillar crypt squamous epithelium supports active viral replication and represents an important source of viral shedding that facilitates person-to-person transmission by both the fecal-oral or oral-oral routes. It may also be a portal for viral entry. A correlation between viral infection and SCARB2 expression appears to be more significant than for PSGL-1 expression.

Fulltext Intraabdominal desmoplastic small round cell tumour in an 11-year-old boy

Ariffin H, Ariffin WA, Wong KT, Ramanujam TM, Lin HP

Singapore Med J, 1997 Apr;38(4):169-71.

PMID: 9269398

A case of desmoplastic small round cell tumour (DSRCT) is presented. This aggressive and rare neoplasm predominantly affects males and is almost exclusively intraabdominal in location. It is unique in that neural, mesenchymal and epithelial markers are co-expressed. Despite multi-modal therapy, the prognosis is extremely poor. The present report details the clinical features and typical pathological findings of DSRCT in an 11-year-old boy, who succumbed to the disease 16 months after diagnosis despite multiple chemotherapeutic regimes.

Fulltext Pulmonary involvement by Hodgkin's disease mimicking pneumonia

Liam CK, Wong KT, Lim YC

Med J Malaysia, 1997 Mar;52(1):84-6.

PMID: 10968059

A 24-year-old man who was initially thought to have nocardiosis of his mediastinal lymph node which progressed to involve his right lung, had to undergo a right pneumonectomy when he failed to respond to treatment with sulphadiazine. Histology of the right lung specimen and a subsequent axillary lymph node biopsy revealed that he actually had lymphocyte-depleted Hodgkin's disease.

Beyond Pattern Recognition: Radiology-Pathology-Clinical Correlation

Wong KT, Tan CT, Lim T

Neuroimaging Clin N Am, 2023 Feb;33(1):225-233.

PMID: 36404045 DOI: 10.1016/j.nic.2022.07.018

Radiology-pathology correlation is essential for multidisciplinary collaboration in diagnosis and understanding the mechanism of CNS damage in infectious processes. The microscopic acute inflammatory processes are well established and are supplemented by a variety of less-invasive microbial and immunohistochemical investigations. Understanding the pathogenesis of pathogen spread and neuroinvasion, vascular and immune-mediated brain, and spinal cord damage are essential for interpreting radiological images.

Fulltext Immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy Chinese children: a report of further observations

Liu L, Mo Z, Liang Z, Zhang Y, Li R, Ong KC, et al.

BMC Med, 2015;13:226.

PMID: 26381232 DOI: 10.1186/s12916-015-0448-7

To investigate the long-term effects on immunity of an inactivated enterovirus 71 (EV71) vaccine and its protective efficacy.

Fulltext Unusual manifestation of cutaneous toxoplasmosis in a HIV-positive patient

Fong MY, Wong KT, Rohela M, Tan LH, Adeeba K, Lee YY, et al.

Trop Biomed, 2010 Dec;27(3):447-50.

PMID: 21399585 MyJurnal

We report a case of unusual cutaneous toxoplasmosis manifestation in a HIV-positive patient. He presented with hard and painful nodular lesions on the arms, hands and chest. Serology tests for anti-Toxoplasma antibody were negative. However, histopathologic examination of the lesion revealed foci of macrophages containing crescent-shaped organisms resembling the zoites of the protozoan parasite Toxoplasma gondii. Ultrastructure examination under electron microscopy and PCR confirmed the organism as T. gondii.

Fatal enterovirus 71 encephalomyelitis

Lum LC, Wong KT, Lam SK, Chua KB, Goh AY, Lim WL, et al.

J Pediatr, 1998 Dec;133(6):795-8.

PMID: 9842048

During an outbreak of hand-foot-mouth disease caused by enterovirus 71 (EV-71) in 1997, 4 children presented with sudden cardiopulmonary collapse and minimal neurologic features. All children received cardiopulmonary resuscitation but died within a few hours of admission. Postmortem studies showed infection by EV-71 with extensive damage to the medulla and pons. We postulate an etiologic link between EV-71 and brainstem encephalomyelitis as the cause of pulmonary edema and death.

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