QUIZ PAGE APRIL 2015 Fever and Encephalopathy in a Kidney Transplant Recipient CLINICAL PRESENTATION
QUIZ PAGE
A 34-year-old man who underwent deceased donor kidney transplantation for chronic glomerulonephritis 10 months prior to admission presented with a fever (101 F) and nonproductive cough that had persisted for 3 days. Pretransplantation serologic testing was negative for HIV (human immunodeficiency virus), hepatitis B virus, hepatitis C virus, and EpsteinBarr virus. The donor’s cytomegalovirus and Epstein-Barr virus status was unknown. Induction therapy with antithymocyte globulin was followed by tacrolimus, mycophenolate mofetil, and prednisolone immunosuppression. Nadir serum creatinine level was 1 mg/dL (corresponding to an estimated glomerular filtration rate of 89 mL/min/ 1.73 m2 as calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation). Prophylactic trimethoprim/sulfamethoxazole and valgancyclovir therapies were continued for 6 and 3 months, respectively. Physical examination revealed a conscious tachypneic patient with wheezes and crackles over the lung bases. Heart sounds were normal without murmurs. Laboratory data showed a white blood cell count of 3,900/mL (neutrophils, 42%; lymphocytes, 51%; monocytes, 6%; and eosinophils, 1%) and platelet count of 175,000/mL. Serum creatinine level had increased to 1.4 mg/dL (estimated glomerular filtration rate, 62 mL/min/ 1.73 m2). Chest radiograph and echocardiogram were normal. Trimethoprim/sulfamethoxazole and valgancyclovir treatment was restarted, and
xviii
levofloxacin was added. Fevers persisted into the second week, when a bitemporal headache of increasing severity developed. Otorhinolaryngologic evaluation showed no abnormality, and no skin rash was apparent. Neurologic consultant found no focal deficits. White blood cell count remained low (3,700-2,700/mL). Cytomegalovirus was undetectable in plasma by polymerase chain reaction (PCR). Magnetic resonance imaging (MRI) revealed multiple diffusion-restricted lesions deep within the brain parenchyma at the splenium and left frontal lobe (Fig 1). Cerebrospinal fluid (CSF) analysis revealed a clear fluid with a cell count of 3/mL, protein level of 18 mg/ dL, and glucose level of 78 mg/dL. Rifampicin, isoniazid, and pyrazinamide treatments were started. Over the next 4 days, his sensorium progressively deteriorated. Repeat computed tomographic scan showed multiple expanding areas of infarctions involving the frontoparietal and occipital lobes (Fig 2). PCR testing of the CSF was negative for tuberculosis, Cryptococcus species, and toxoplasmosis.
- What are the diagnostic considerations of
brain lesions, fever, and altered mental status in a kidney transplant recipient? - What features in the MRI hold the key to
the diagnosis? - What is the treatment?
Am J Kidney Dis. 2015;65(4):xviii-xxi
Figure 1. Magnetic resonance imaging shows diffusion-restricted lesion in (A) the splenium of corpus callosum (arrow) and (B) deep left frontal lobe (arrow).
Figure 2.
Computed tomographic scan shows multiple large areas of hypodense lesions in the brain (arrows).
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Am J Kidney Dis. 2015;65(4):xviii-xxi
QUIZ PAGE APRIL 2015
ANSWERS
DISCUSSION - What are the diagnostic
considerations of brain lesions, fever, and altered mental status in a kidney transplant recipient? This patient’s clinical profile fits with a diagnosis of an ongoing infectious, inflammatory, or malignant process involving the central nervous system (CNS). Infective endocarditis is a strong possibility given the multifocal nature of the infarcts, but an echocardiogram did not reveal vegetations. Mycobacterial or invasive fungal infections of the CNS vasculature due to aspergillus or mucormycosis can behave in a similar fashion. The nasopharynx and sinuses were free of fungal colonization in this patient. Primary CNS lymphoma also is a possibility, but the rapidity of clinical deterioration makes it less likely. Finally, varicella-zoster virus (VZV) angiopathy should be considered. - What features in the MRI
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hold the key to the diagnosis? Deep-seated infarctions involving the grey-white matter junction are the hallmark of VZV angiopathy.1 A history of chicken pox 6 months prior to kidney transplantation was obtained later from his sister, which led us to the diagnosis. Serum immunoglobulin G (IgG) VZV antibody level was 286 IU/mL, and that of the CSF was 104 IU/mL. CSF PCR
xx
for VZV was negative, as seen in 20% of cases. The diagnosis is made by demonstrating intrathecal synthesis of virus-specific IgG with enzyme-linked immunosorbent assay.2,3 Intrathecally produced VZV antibodies are measured by an elevated antibody index, which is the ratio between CSF and serum levels of virusspecific antibodies. In this case, the CSF to serum ratio of total IgG was, at 1.6, diagnostic. VZV can lie dormant in the cranial nerve nuclei before reactivating at a later time facilitated by immunosuppression. It is the only virus that invades the CNS arteries, directly giving rise to multiple deep-seated infarctions in the brain parenchyma. Primary invasion of the CNS vasculature recently has been recognized with protean manifestations, including infarctions, aneurysms, and cerebral hemorrhage. These result in a broad spectrum of neurologic symptoms ranging from headaches to acute hemiplegia to changes in mental status.4 Histopathologic examination of infected temporal arteries reveals initial viral invasion of the tunica adventitia, followed by involvement of the media and intima. Intimal entry results in myointimal proliferation, stenosis, and thrombosis. CSF analysis can be bland, as was seen in our case. Characteristic rash may be absent (zoster sine herpete) in up to 30% of immunosuppressed cases, leading to diagnostic delays.5
- What is the treatment?
If the condition is suspected and detected early, a 2-week course of intravenous acyclovir (10 mg/kg every 8 hours) can be lifesaving. Our patient died of his illness following multiorgan failure and shock.
FINAL DIAGNOSIS CNS angiopathy due to varicella zoster virus.
REFERENCES 1. Amlie-Lefond C, Jubelt B. Neurologic manifestations of varicella zoster virus infections. Curr Neurol Neurosci Rep. 2009;9(6): 430-434. 2. Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007;68(13):1069-1073. 3. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem. 1991;37(7):1153-1160. 4. Chang GY. Clinical recognition of varicella zoster virus vasculopathy. Eur Neurol. 2012;67(5): 297-299. 5. Jantsch J, Schmidt B, Bardutzky J, Bogdan C, Eckardt K, Raff U. Lethal varicella-zoster virus reactivation without skin lesions following renal transplantation. Nephrol Dial Transplant. 2011;26(1):365-368. CASE PROVIDED AND AUTHORED BY Krishnaswamy Sampathkumar, MD, DNB, DM, FRCP (Glasgow),
Am J Kidney Dis. 2015;65(4):xviii-xxi
Arunachalam Prabhakar, MD, DNB, and Chinnathambi Vijay Anand, MD, DNB, Meenakshi Mission Hospital and Research Centre, Madurai, India. Address correspondence to Krishnaswamy Sampathkumar, MD, DNB, DM, FRCP (Glasgow),
http://dx.doi.org/10.1053/j.ajkd.2014. 11.028 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
xxi
QUIZ PAGE
Am J Kidney Dis. 2015;65(4):xviii-xxi
Department of Nephrology, Meenakshi Mission Hospital and Research Centre, Lake Area, Melur Road, Madurai, Tamil Nadu 625 107, India. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc.
QUIZ PAGE
A 34-year-old man who underwent deceased donor kidney transplantation for chronic glomerulonephritis 10 months prior to admission presented with a fever (101 F) and nonproductive cough that had persisted for 3 days. Pretransplantation serologic testing was negative for HIV (human immunodeficiency virus), hepatitis B virus, hepatitis C virus, and EpsteinBarr virus. The donor’s cytomegalovirus and Epstein-Barr virus status was unknown. Induction therapy with antithymocyte globulin was followed by tacrolimus, mycophenolate mofetil, and prednisolone immunosuppression. Nadir serum creatinine level was 1 mg/dL (corresponding to an estimated glomerular filtration rate of 89 mL/min/ 1.73 m2 as calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation). Prophylactic trimethoprim/sulfamethoxazole and valgancyclovir therapies were continued for 6 and 3 months, respectively. Physical examination revealed a conscious tachypneic patient with wheezes and crackles over the lung bases. Heart sounds were normal without murmurs. Laboratory data showed a white blood cell count of 3,900/mL (neutrophils, 42%; lymphocytes, 51%; monocytes, 6%; and eosinophils, 1%) and platelet count of 175,000/mL. Serum creatinine level had increased to 1.4 mg/dL (estimated glomerular filtration rate, 62 mL/min/ 1.73 m2). Chest radiograph and echocardiogram were normal. Trimethoprim/sulfamethoxazole and valgancyclovir treatment was restarted, and
xviii
levofloxacin was added. Fevers persisted into the second week, when a bitemporal headache of increasing severity developed. Otorhinolaryngologic evaluation showed no abnormality, and no skin rash was apparent. Neurologic consultant found no focal deficits. White blood cell count remained low (3,700-2,700/mL). Cytomegalovirus was undetectable in plasma by polymerase chain reaction (PCR). Magnetic resonance imaging (MRI) revealed multiple diffusion-restricted lesions deep within the brain parenchyma at the splenium and left frontal lobe (Fig 1). Cerebrospinal fluid (CSF) analysis revealed a clear fluid with a cell count of 3/mL, protein level of 18 mg/ dL, and glucose level of 78 mg/dL. Rifampicin, isoniazid, and pyrazinamide treatments were started. Over the next 4 days, his sensorium progressively deteriorated. Repeat computed tomographic scan showed multiple expanding areas of infarctions involving the frontoparietal and occipital lobes (Fig 2). PCR testing of the CSF was negative for tuberculosis, Cryptococcus species, and toxoplasmosis.
- What are the diagnostic considerations of
brain lesions, fever, and altered mental status in a kidney transplant recipient? - What features in the MRI hold the key to
the diagnosis? - What is the treatment?
Am J Kidney Dis. 2015;65(4):xviii-xxi
Figure 1. Magnetic resonance imaging shows diffusion-restricted lesion in (A) the splenium of corpus callosum (arrow) and (B) deep left frontal lobe (arrow).
Figure 2.
Computed tomographic scan shows multiple large areas of hypodense lesions in the brain (arrows).
xix
QUIZ PAGE
Am J Kidney Dis. 2015;65(4):xviii-xxi
QUIZ PAGE APRIL 2015
ANSWERS
DISCUSSION - What are the diagnostic
considerations of brain lesions, fever, and altered mental status in a kidney transplant recipient? This patient’s clinical profile fits with a diagnosis of an ongoing infectious, inflammatory, or malignant process involving the central nervous system (CNS). Infective endocarditis is a strong possibility given the multifocal nature of the infarcts, but an echocardiogram did not reveal vegetations. Mycobacterial or invasive fungal infections of the CNS vasculature due to aspergillus or mucormycosis can behave in a similar fashion. The nasopharynx and sinuses were free of fungal colonization in this patient. Primary CNS lymphoma also is a possibility, but the rapidity of clinical deterioration makes it less likely. Finally, varicella-zoster virus (VZV) angiopathy should be considered. - What features in the MRI
QUIZ PAGE
hold the key to the diagnosis? Deep-seated infarctions involving the grey-white matter junction are the hallmark of VZV angiopathy.1 A history of chicken pox 6 months prior to kidney transplantation was obtained later from his sister, which led us to the diagnosis. Serum immunoglobulin G (IgG) VZV antibody level was 286 IU/mL, and that of the CSF was 104 IU/mL. CSF PCR
xx
for VZV was negative, as seen in 20% of cases. The diagnosis is made by demonstrating intrathecal synthesis of virus-specific IgG with enzyme-linked immunosorbent assay.2,3 Intrathecally produced VZV antibodies are measured by an elevated antibody index, which is the ratio between CSF and serum levels of virusspecific antibodies. In this case, the CSF to serum ratio of total IgG was, at 1.6, diagnostic. VZV can lie dormant in the cranial nerve nuclei before reactivating at a later time facilitated by immunosuppression. It is the only virus that invades the CNS arteries, directly giving rise to multiple deep-seated infarctions in the brain parenchyma. Primary invasion of the CNS vasculature recently has been recognized with protean manifestations, including infarctions, aneurysms, and cerebral hemorrhage. These result in a broad spectrum of neurologic symptoms ranging from headaches to acute hemiplegia to changes in mental status.4 Histopathologic examination of infected temporal arteries reveals initial viral invasion of the tunica adventitia, followed by involvement of the media and intima. Intimal entry results in myointimal proliferation, stenosis, and thrombosis. CSF analysis can be bland, as was seen in our case. Characteristic rash may be absent (zoster sine herpete) in up to 30% of immunosuppressed cases, leading to diagnostic delays.5
- What is the treatment?
If the condition is suspected and detected early, a 2-week course of intravenous acyclovir (10 mg/kg every 8 hours) can be lifesaving. Our patient died of his illness following multiorgan failure and shock.
FINAL DIAGNOSIS CNS angiopathy due to varicella zoster virus.
REFERENCES 1. Amlie-Lefond C, Jubelt B. Neurologic manifestations of varicella zoster virus infections. Curr Neurol Neurosci Rep. 2009;9(6): 430-434. 2. Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007;68(13):1069-1073. 3. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem. 1991;37(7):1153-1160. 4. Chang GY. Clinical recognition of varicella zoster virus vasculopathy. Eur Neurol. 2012;67(5): 297-299. 5. Jantsch J, Schmidt B, Bardutzky J, Bogdan C, Eckardt K, Raff U. Lethal varicella-zoster virus reactivation without skin lesions following renal transplantation. Nephrol Dial Transplant. 2011;26(1):365-368. CASE PROVIDED AND AUTHORED BY Krishnaswamy Sampathkumar, MD, DNB, DM, FRCP (Glasgow),
Am J Kidney Dis. 2015;65(4):xviii-xxi
Arunachalam Prabhakar, MD, DNB, and Chinnathambi Vijay Anand, MD, DNB, Meenakshi Mission Hospital and Research Centre, Madurai, India. Address correspondence to Krishnaswamy Sampathkumar, MD, DNB, DM, FRCP (Glasgow),
http://dx.doi.org/10.1053/j.ajkd.2014. 11.028 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
xxi
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Am J Kidney Dis. 2015;65(4):xviii-xxi
Department of Nephrology, Meenakshi Mission Hospital and Research Centre, Lake Area, Melur Road, Madurai, Tamil Nadu 625 107, India. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc.
