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  Table of Contents    
CLINICOPATHOLOGIC CONFERENCE  
Year : 2017  |  Volume : 60  |  Issue : 1  |  Page : 92-96
A 54-year-old male with rapidly progressive neurologic syndrome: Clinicopathologic correlation of a rare diagnosis


1 Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Department of Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India

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Date of Web Publication14-Feb-2017
 

   Abstract 

Diagnosis of systemic lupus erythematosus (SLE) as primary presentation with central nervous system involvement as a rapidly progressive neurologic syndrome is extremely rare. We present a rare case of a 54-year-old hypertensive male patient, who presented with a fulminant neurologic syndrome. He presented with cerebellar and meningeal signs, aseptic meningitis and had a rapid downhill course following admission. A postmortem revealed feature of systemic connective tissue fulfilling diagnostic criteria of SLE with lupus cerebritis.

Keywords: Chronic meningoencephalitis, systemic lupus erythematosus, lupus cerebritis, renal cortical scarring

How to cite this article:
Mutreja D, Moorchung N, Gupta S, Saxena R, Doshetty RS, Nandi B. A 54-year-old male with rapidly progressive neurologic syndrome: Clinicopathologic correlation of a rare diagnosis. Indian J Pathol Microbiol 2017;60:92-6

How to cite this URL:
Mutreja D, Moorchung N, Gupta S, Saxena R, Doshetty RS, Nandi B. A 54-year-old male with rapidly progressive neurologic syndrome: Clinicopathologic correlation of a rare diagnosis. Indian J Pathol Microbiol [serial online] 2017 [cited 2017 Mar 30];60:92-6. Available from: http://www.ijpmonline.org/text.asp?2017/60/1/92/200026



   Clinical Protocol Top


A 54-year-old male presented with a history of lethargy, intermittent headaches, forgetfulness, and mood change in the form of withdrawn behavior of 15 days duration. There was associated history of imbalance while walking for 4–5 days, giddiness and slurring of speech of 2 days duration. One-day prior his wife had noticed intermittent, transient rhythmic movement of right hand during which he would become unresponsive.

He was a known case of hypertension on medication with tablet amlodipine and atenolol for 5 years. His wife had been treated for pulmonary tuberculosis (TB) 8 years ago.


   Clinical Examination and Investigations Top


Clinical examination revealed a middle-aged male with normal higher mental functions, who was conscious and obeying commands. Pulse rate was 54/min, blood pressure (BP) - 138/90 mm of Hg, and mild pallor was noted. Central nervous system examination revealed bilateral VI th cranial nerve and right III rd nerve palsies and left upper motor neuron type facial nerve palsy. Neck stiffness, dysarthria, and positive Romberg's test with ataxic gait were seen. Nystagmus was present. Fundus examination was normal.

Investigations revealed normocytic normochromic anemia, mild thrombocytopenia, increased serum proteins, and hyponatremia. Activated partial thromboplastin time (APTT) was prolonged. Serum bilirubin, transaminases, renal function tests, and routine urine examination were normal [Table 1]. Cerebrospinal fluid (CSF) evaluation revealed elevated proteins (84 mg/dL) with increased globulins, lymphocytic pleocytosis (total cells: 135/µL, White blood cells: 60 cells/µL). Blood and CSF sugar were 104 and 52 mg/dL, respectively. Adenosine deaminase (ADA) level in CSF was normal. Polymerase chain reaction (PCR) for mycobacteria, cytomegalovirus (CMV), and herpes simplex virus (HSV) were negative. Staining for microorganisms was negative and cultures were sterile. Malignant cell cytology, cryptococcal antigen, tests for syphilis, toxoplasma, rubella, CMV, and herpes virus on CSF were negative. Initial electroencephalogram (EEG) showed slowing with no epileptiform discharges.
Table 1: Laboratory investigations*

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Imaging studies (noncontrast computed tomography [NCCT] and contrast-enhanced magnetic resonance imaging [MRI]) of the brain were normal. Ultrasound abdomen revealed cholelithiasis. Carotid Doppler revealed atheromatous plaques. Chest roentgenogram was normal.


   Course in the Hospital Top


The patient was managed as a case of tubercular meningitis with broad spectrum antibiotics, empirical antitubercular treatment (ATT), acyclovir, steroids, antiepileptics, and supportive care. Hyperpigmented plaque-like lesions over extensor aspect of both arms were noted and dermatology review opined endogenous eczema.

On day 3, he developed increasing drowsiness and CO2 retention. Imaging of chest and abdomen showed bilateral pleuropulmonary fibrosis suggestive of old TB and accentuated fetal lobulation of kidneys with cholelithiasis.

Mannitol and 3% NaCl infusion were added. Repeat NCCT brain was normal. On day 4, a repeat CSF tap showed similar findings. He developed severe respiratory acidosis requiring intubation and mechanical ventilation. Repeat EEGs done thereafter showed generalized slowing, multifocal epileptiform discharges with the absence of periodic lateralized epileptiform discharges (PLEDs). He showed poor response to ATT.

On day 5, his sensorium worsened further and he slipped into the deep comatose state. He showed features of increased intracranial tension (ICT) and developed myoclonic jerks. Midazolam infusion, high-dose steroids, and intravenous immunoglobulins (IVIGs) were added. Tumor markers were normal. A bedside echocardiogram showed normal ejection fraction of 70% with concentric left ventricular hypertrophy. He required inotropic support and was having intermittent hypotensive episodes despite being on inotropic support. A repeat NCCT brain on day 6 revealed features of diffuse cerebral edema with increased ICT.

On day 7, increased urinary output was noted. Desmopressin nasal spray was administered. He was tracheostomized in anticipation of prolonged ventilation. He had recurrent focal seizures and continued hypotension. Further investigations revealed positive antinuclear antibody (ANA) and anti-cyclic citrullinated protein (CCP) antibodies by ELISA. As the patient was hemodynamically unstable positron emission tomography scan could not be done.

On day 9, he developed thick tenacious secretions from tracheal aspirate with poor neurologic recovery. Imaging of chest revealed consolidation of lower zones. On day 10, he deteriorated further, developed high-grade fever, leukocytosis, and multidrug resistant Klebsiella pneumoniae was isolated from blood and tracheal aspirate cultures. On day 14, he died of ventilator-associated pneumonia, multiorgan failure, and severe sepsis.


   Unit's Final Diagnosis Top


Chronic meningoencephalitis, likely tubercular etiology. Cause of death: Ventilator-associated pneumonia with sepsis and multiorgan failure.


   Discussion on Clinical Protocol by Professor Medicine Top


A middle-aged male, known case of hypertension on medication, presented with a progressive neurologic syndrome of 15 days history with possible involvement of cortex, brainstem, cerebellum, and extraaxial brainstem. Withdrawn behavior and forgetfulness were suggestive of temporal lobe involvement and right III rd and left VII th cranial nerve palsies with neck stiffness suggested extraaxial brainstem (meningeal) involvement. Imbalance while walking, dysarthria, nystagmus, and ataxic gait with positive Romberg's test suggested cerebellar involvement.

Evaluation revealed CSF abnormalities indicative of aseptic meningitis. Encephalitic signs in form of early onset seizures, neurological deficit, and alteration of sensorium were suggested meningoencepahlitis. Common infectious etiologies were considered, namely, tubercular and viral meningoencephalitis. Noninfectious etiologies were also considered in the differential diagnoses including neoplastic/paraneoplastic syndromes, noninfective inflammatory conditions, namely, sarcoidosis, lupus, and rarer diagnoses such as isolated granulomatous angitis of the CNS, autoimmune encephalitis, and drug hypersensitivity were other differential diagnoses.

Points favoring a tubercular etiology were family history of TB, CT chest findings of bilateral pleuropulmonary fibrosis and CSF abnormalities. Points against it were the absence of fever, an extremely rapid downhill course, normal MRI, negative CSF ADA and PCR.

Viral encephalitis, especially HSV was considered in view of the clinical picture. However, the features against this were the absence of fever, the absence of PLEDs on EEG, a negative CSF PCR and normal MRI. Parasitic and fungal infections were clinically excluded based on immunocompetent status, absence of fever and MRI findings.

Autoimmune encephalitis secondary to neoplastic or paraneoplastic syndrome were considered in view of limbic encephalitis-like presentation without fever. The clinical profile against this diagnosis was negative imaging, CSF and tumor marker screen. Hypertensive encephalopathy was also considered at admission, however, was unlikely as the BP recorded was never high.

Meningoencephalitis associated with connective tissue disorder or a vasculitis were thought of in view of a positive ANA, anti-CCP and an eczematous skin rash, anemia, and thrombocytopenia at presentation. Further autoimmune antibody screen to exclude autoimmune encephalitis were ordered. However, the points against the same were male gender, a rapid fulminant course, no preceding history, and normal MRI brain. The management comprised ATT along with supportive measures. High-dose steroids and IVIGs were administered.


   Final Clinical Diagnosis Top


  • Chronic meningoencephalitis: Tubercular meningoencephalitis
  • Differential diagnosis of (a) secondary autoimmune meningoencephalitis (b) paraneoplastic process due to an occult malignancy/limbic encephalitis
  • Terminal event: Sepsis with multiorgan failure.
  • Comorbidity: Hypertension.



   Pathology Protocol by Associate Professor Pathology Top


Gross findings

At autopsy, body of a middle aged male with anasarca was seen. There were bilateral pleural effusions and turbid peritoneal effusion.

The left and right kidneys were enlarged and markedly congested weighing 375 and 300 g, respectively [Figure 1]a and [Figure 1]b. Capsules were nonadherent and on stripping away, multiple deep and superficial cortical scars continuing into each other were seen [Figure 1]c and [Figure 1]d. Cut surface showed thinning of cortex with distinct cortical-medullary demarcation [Figure 1]e. There was no dilatation or deformation of renal pelvis nor any stones or strictures. Lower lobes of both lungs were congested and oozed blood stained fluid on pressure. The apex of the right lung showed a depressed irregular scar [Figure 1]f. Left anterior descending branch of coronary showed narrowing of lumen with atherosclerotic plaque. Atherosclerotic plaques were also seen in the great vessels. No cardiac valvular abnormalities, hypertrophy of ventricles or features of endocarditis were seen. The liver and spleen were enlarged weighing 1800 and 300 g respectively. Cut surface of spleen was congested. The brain weighed 1300 g, appeared edematous, and showed small bleed over left temporal lobe [Figure 1]g. The undersurface of brain was normal. No basal exudates, fibrinopurulent discharges or tubercles were seen [Figure 1]h. Cut surface of the brain showed multiple punctate hemorrhages in thalamus, midbrain, and cerebellum [Figure 1]i and [Figure 1]j. No necrotic foci were seen. Gastrointestinal tract, endocrine, lymphoreticular system, and testes and were unremarkable on gross.
Figure 1: (a and b) Enlarged congested kidneys. (c and d) Kidneys after stripping away capsule showing multiple deep and superficial cortical scars. (e) Cut surface of kidney showing distinct cortical-medullary demarcation with normal renal pelvis. (f) Apex of the right lung showed a depressed irregular scar (arrow). (g) Edematous brain surface with small bleed over left temporal lobe. (h) Undersurface of brain without any basal exudates, fibrinopurulent discharges or tubercles. (i and j) Formalin-fixed slice of brain and thalamus showing multiple punctate hemorrhages

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Microscopic findings

Stained sections from kidneys showed hypercellular glomeruli with focal segmental mesangial proliferation (active lesions) admixed with sclerosed glomeruli (chronic lesions). Tubules showed casts with proximal tubular necrosis. Chronic interstitial inflammation was seen in areas of scarring. Blood vessels showed onion skinning of media. Bacterial colonies were present in some glomeruli [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d.
Figure 2: (a and b) Hypercellular glomeruli with focal and segmental mesangial proliferation (arrows). (c) Sclerosed glomeruli (arrows) with tubular casts and inflammation. (d) Onion skinning of media (×400). (e) Alveolar wall thickening and features of plexiform pulmonary arteriopathy (×400). (f) Apex of right lung showing foreign body giant cells (×1000). (g) Liver showing fibrosis with portal to portal extension (×100). (h) Bile ductular proliferation and chronic portal inflammation (×1000). (i) Small vessel vasculopathy in brain (×400). (j) Complicated atherosclerotic plaque in left coronary (×100)

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Sections from upper lobe of lung showed alveolar wall thickening and features of plexiform pulmonary arteriopathy [Figure 2]e. Sections from scarred area apex of right lung showed pleural thickening with the presence of foreign body giant cells [Figure 2]f.

Liver showed features of fibrosis with portal to portal extension [Figure 2]g. Bile ductular proliferation, portal inflammation were seen [Figure 2]h. Spleen showed marked expansion of the red pulp and diminution of white pulp. Sections from meninges showed mild perivascular lymphocytic inflammation. Brain showed small vessel vasculopathy in the form of congested dilated capillaries with inflammatory cells [Figure 2]i and cortical microinfarcts. No viral associated cytopathic effects were seen.

Sections from coronaries showed complicated atherosclerotic plaques with luminal narrowing [Figure 2]j.

Postmortem serologic tests (done on antemortem samples) revealed positive ANA by immunofluorescence and anti dSDNA in high titers.


   Final Diagnosis Top


Primary lupus cerebritis in an undiagnosed case of systemic lupus erythematosus (SLE) with sepsis and multiorgan failure.

Clinicopathologic correlation

Postmortem findings of deep cortical scarring in the kidney with focal segmental mesangioproilferative glomerulonephritis with both active and chronic glomerular lesions in the presence of positive ANA and anti-dSDNA in high titers, are suggestive of class III lupus nephritis.[1]

Anemia, thrombocytopenia, prolonged APTT (lupus anticoagulant), presence of a skin rash and multisystem involvement on the form of chronic hepatitis, pulmonary fibrosis with plexiform pulmonary angitis are added features of SLE. Positive anti-CCP antibodies have been reported in up to 15% of SLE patients.[2],[3]

All the CNS symptoms including cognitive dysfunction, cranial nerve palsies, cerebellar and meningeal signs and aseptic meningitis can be explained by SLE.[4] Mild hyponatremia may result from SIADH. Normal urine sediment and serum creatinine may represent silent lupus nephritis.[5],[6]

Thus taking clinical and autopsy findings, the defining criteria of SLE were fulfilled.[7],[8]


   Brief Comment on Central Nervous System Lupus Top


Inflammation of the brain secondary to autoantibody-mediated neurotoxicity, small vessel noninflammatory vasculopathy, and cytokine-induced neurotoxicity are understood to be the principal pathogenic factors responsible for CNS lupus which is associated with a poor prognosis and high mortality.[4],[9]

The stated occurrence of neurologic manifestations in SLE varies greatly in literature, ranging from 12% to 95% in different studies.[10],[11] The higher prevalence in various studies account for the nonspecific clinical features such as headache and depression being taken into account. Severe CNS involvement in SLE at presentation like in this case is relatively rare.[10]

In this case, CNS involvement resembling limbic encephalitis and characteristic histopathologic finding described in lupus brains at autopsy of small vessel thrombotic-vasculopathy [12] were seen. Despite high dose steroids and IVIG, the patient had a complicated course due to ventilator-associated pneumonia. To conclude, lupus cerebritis in an undiagnosed SLE with aseptic meningitis is rather uncommon and can cause diagnostic dilemma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521-30.  Back to cited text no. 1
    
2.
Skare TL, Nisihara R, Barbosa BB, da Luz A, Utiyama S, Picceli V. Anti-CCP in systemic lupus erythematosus patients: A cross sectional study in Brazilian patients. Clin Rheumatol 2013;32:1065-70.  Back to cited text no. 2
    
3.
Kakumanu P, Sobel ES, Narain S, Li Y, Akaogi J, Yamasaki Y, et al. Citrulline dependence of anti-cyclic citrullinated peptide antibodies in systemic lupus erythematosus as a marker of deforming/erosive arthritis. J Rheumatol 2009;36:2682-90.  Back to cited text no. 3
    
4.
Kivity S, Agmon-Levin N, Zandman-Goddard G, Chapman J, Shoenfeld Y. Neuropsychiatric lupus: A mosaic of clinical presentations. BMC Med 2015;13:43.  Back to cited text no. 4
    
5.
Zabaleta-Lanz M, Vargas-Arenas RE, Tápanes F, Daboin I, Atahualpa Pinto J, Bianco NE. Silent nephritis in systemic lupus erythematosus. Lupus 2003;12:26-30.  Back to cited text no. 5
    
6.
Zabaleta-Lanz ME, Muñoz LE, Tapanes FJ, Vargas-Arenas RE, Daboin I, Barrios Y, et al. Further description of early clinically silent lupus nephritis. Lupus 2006;15:845-51.  Back to cited text no. 6
    
7.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.  Back to cited text no. 7
    
8.
The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599-608.  Back to cited text no. 8
    
9.
Ramage AE, Fox PT, Brey RL, Narayana S, Cykowski MD, Naqibuddin M, et al. Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus. Arthritis Rheum 2011;63:3048-57.  Back to cited text no. 9
    
10.
Kampylafka EI, Alexopoulos H, Kosmidis ML, Panagiotakos DB, Vlachoyiannopoulos PG, Dalakas MC, et al. Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus: A 3-year prospective study of 370 patients. PLoS One 2013;8:e55843.  Back to cited text no. 10
    
11.
Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G. Neuropsychiatric syndromes in systemic lupus erythematosus: A meta-analysis. Semin Arthritis Rheum 2011;41:1-11.  Back to cited text no. 11
    
12.
Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-Romo D, Stallworth CL, et al. Neuropsychiatric syndromes in lupus: Prevalence using standardized definitions. Neurology 2002;58:1214-20.  Back to cited text no. 12
    

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Correspondence Address:
Deepti Mutreja
Department of Pathology, Command Hospital Air Force, Bengaluru - 560 007, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.200026

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