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Home , Actinobacteridae, Actinomycosis, Diphtheria, Nocardia, Nocardiosis

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Review Article *Corresponding author RR Sharma, Senior Consultant Neurosurgeon, PO Box-397, PC-118, Al Harthy Complex, Qurum, Muscat, Cranio-Cerebral in Oman, Tel: 00 968 24567339/24811688; 00 968 99241189; Email: Submitted: 11 July 2017 and : Accepted: 05 August 2017 Published: 06 August 2017 Assessment and Management Copyright © 2017 Sharma et al. ISSN: 2573-1289

Strategies OPEN ACCESS Rewati Raman Sharma1* and Apollina Sharma2 Keywords 1 Department of Neurosurgery, Atlas Hospitals, Oman • Nocardiosis; Actinomycosis; Cerebral; ; 2 Graduate Student International Masters of Health Leadership, McGill University, Granulomas; Management strategies; Morbidities; Canada Mortality; Prognosis

Abstract The CNS , such as nocardiosis and actinomycosis, are extremely rare conditions secondary to the primary focus elsewhere i.e., commonly in the , skin, oro-dental areas, paranasal sinuses, and cervico-facial regions; less commonly abdomen and rarely, the pelvic region. These CNS infections are usually sub-acute or chronic disease processes and only occasionally, an acute presentation does occur mainly in nocardiosis. Brain abscesses in nocardiosis and actinomycosis are usually due to chronically continued inflammation and gradual collection of the infected material with and without granulomatous component. Acute and sub-acute clinical presentations usually occur in cerebral abscesses and the chronic clinical features are seen more in granulomas. Interestingly, in many patients, both abscesses and granulomas coexist. The CNS infections can be insidious in onset, slowly progressive and without usual features of systemic . The late clinical presentation may be with headaches, behavioral changes, focal neurological deficits, raised intracranial pressure (progressive headaches, episodic transient loss of vision (visual obscuration), neck stiffness, and vomiting) and . The brain imaging (Computerized Tomography of the head (CT head) and Magnetic resonance imaging (MRI)) is carried out to evaluate the extent of the CNS involvement with cerebral mass lesions, such as cerebral abscesses and granulomas or other parenchymal features of the raised intracranial pressure. The hematological, biochemical and microbiological studies help in further defining the etiology, local/general spreads and the secondary effects. Fortunately, these infections show good response to the appropriate such as co-trimoxazole which is the drug of choice (DOC) for nocardiosis and -G (DOC) for actinomycosis with excellent results as the cure is achievable in some patients. Therefore, the overall management includes the control of CNS infection, elimination of the primary focus, and containment of dissemination. Mainly the anti-microbial drugs, analgesics, anti-emetics and the surgical interventions are used wherever indicated. Surgical management consists of image guided aspirations of cerebral abscesses and excision of granulomas as well as debridement of the involved tissues. Unfortunately, despite much advancement in the modern diagnostics and therapeutics, there is still appreciable morbidity. These patients need long periods of treatment and the mortality of 20-30% is still high. In future, we need to focus on the preventive measures (public educational activities, immune-prophylaxis and chemo-prophylaxis), as well as on the modern diagnostics and appropriate treatment strategies to achieve optimum results.

INTRODUCTION Actinomycetes, distributed worldwide, are Gram positive with cutaneous sinus tracts draining sulfur granules. These opportunistic infections, although in rare instances, secondarily immunecause solitary competent or multiple individuals. brain abscesses and granulomas in bacilli in branching filaments which are essentially consisting of immune compromised patients but rarely, cause infections in the vegetative bacterial cells contiguously arrangedNocardia in long (aerobic) chains CLASSIFICATION [3-5] and therefore, superficially (anaerobic). resembling thebacillus appearance is a weak of fungi acid [1-3]. The common ones belong to of Edmond I E Nocard (French veterinarian (1850-1903) in Actinomycetes in which stagnant water [2,3]. Actinomyces bacillus is also present in the fast organism present in the soil, decaying vegetation, and . 1888) discovered aerobic acid fast were named by Trevisan as Soon afterwards soil and found as normal flora in the mouth and intestine. Both, compromised individuals. Nocardia bacillus Eppinger in 1891, had described primary pulmonary nocardiosis opportunistic usually causing infections in immune and secondary/ metastatic cerebral abscess in Actinobacteriaa glass blower. are Actinomyces primarily causes pulmonary, and less commonly, the cutaneous and paranasal Among the Gram positive group of bacteria, sinus infections; whereas, commonly results in classified into three groups: Actinomycineae, Corynebacterineae oro-dental, cervico-facial, cranio-facial and intestinal abscesses and Bifido-bacteriaceae. Actinomycineae is further subclassified Cite this article: Sharma RR, Sharma A (2017) Cranio-Cerebral Abscesses in Nocardiosis and Actinomycosis: Assessment and Management Strategies. JSM Brain Sci 2(2): 1013. Sharma et al. (2017) Email:

Central Bringing Excellence in Open Access into and Propioni-bacteriaceae: Actinomyces belongs to the former and Propionibacterium acnes to the latter. Corynebacterineae is also further subdivided into (Tuberculous bacilli, Lepra bacilli), (N. asteroides, N. farcinica, N. brasilliences) and Corynebacteriaceae ( ). Majority of these organisms are basically opportunistic bacteria. In broad terms, the clinically important Gram positive bacilli can 1.also Spore be classified forming bacilli:into three broad groups: bacilli 2. Non-spore forming bacilli: Corynebacterium, Listeria, Lactobacillus Figure 1 Nocardial Pulmonary abscess in the left upper lobe. Actinomyces, Nocardia

BRAIN3. Branching ABSCESSES filamentous DUE bacilli: TO [3- the bone at the site of the trauma. Hematogenous or contiguous 6] nasal sinuses and oral cavity. It is more common in immune There are many Gram positive bacteria belonging to spread of infection to the CNS occurs from the lungs, skin, para- Actinobacteria; however, amongst them, the organisms most lymphoma, cytotoxic drugs, immune suppression, pulmonary commonly causing the CNS infections are Nocardia and alveolarcompromised proteinosis, hosts (diabetes sarcoidosis, mellitus, ulcerative steroid therapy, colitis, leukemia, intestinal Actinomyces. There are many similarities and differences in lypodystrophy, collagen diseases, etc.) but only 15-30% cases the clinical characteristics of nocardiosis and actinomycosis occur in immune-competent individuals. Nocardia species is, which are important to be realized for their proper assessment, therefore, considered primarily as opportunistic . diagnosis and management. Clinical symptomatology [7-10] THE CNS NOCARDIOSIS: [3-7] Nocardiosis affects men (60-70%) more than women (30- Introduction 40%) in their middle ages (fourth through sixth decades of life). It occurs in three primary clinical syndromes in order of Nocardiosis, although a rare infection caused by Actinomycetes frequency: pulmonary (70-75% cases), cutaneous (20-25%), species of Nocardia, is ubiquitous with worldwide distribution. and subcutaneous such as mycetoma of the foot and paranasal As stated earlier, Nocardia bacillus is a common habitant in the sinuses (5-10%). Nocardia soil, decaying vegetation and stagnant water. They are important neural tissues. About 25-40 % cases of systemic nocardiosis environmental saprophytes with excellent growth potentials develop CNS infections and aboutspecies 10-15% has special cases affinityhave the for renal the over a wide range of temperature. Nocardia species are strictly problems. Interestingly, within the cerebro-spinal parenchyma, aerobic Actinomycetes, a large diverse group of bacteria that nocardial infection occurs insidiously without any symptom initially and then spreads slowly with development of the fungi. Nocardia progressive symptoms giving an impression of an evolving mass appear on microscopy as branching filamentous cells mimicking lesion such as a brain or spinal tumor. There are many forms decolorized withtherefore 1% of sulphuric appears acid. as a thin, less than 1µm thick of secondary CNS nocardial lesions: single abscess, multiple gram positive branching filament. It is focally acid fast when brain abscesses, diffuse cerebritis, and meningitis, granulomas Types of nocardia species The common human pathogenic Nocardia species are less common presentation of nocardiosis as compared to the mimicking neoplasms, vasculitis, and strokes. Meningitis is a N. asteroides, N. farcinica, N. nova, N. brasiliensis, N. pseudo- brain abscesses and granulomas. The clinical presentation of CNS brasiliensis, N. otitidiscaviarum and N. transvalensis. N. asteroidis nocardiosis is therefore commonly due to the local mass effects and, closely resembling, N. farcinica cause most human infections of an abscess and a granuloma. The spinal cord involvement is (80-90 %) but N. brasiliensis is a common in Central the least common among all clinical CNS presentations. and South America. In USA alone, yearly about 900-1100 cases In substantial number of cases, the common clinical features are reported. Among all varieties of Nocardia species, Nocardia farcinica appears to be more virulent [5-8] inof initial bacterial presentations inflammation, of the such CNS as nocardiosis. fever, rigors, Therefore, sweating, in The , dissemination and co-morbid theheadaches, initial clinicaltoxic look, stages, vomits, the neck diagnosis stiffness, and etc the may treatment be missing of etiological factors [7-8] The transmission of Nocardia bacilli is usually airborne, or nocardiosis become very difficult and its spread in CNS becomes caused by direct contact, vectors, trauma, and endo-vascular uncheckedThe usual to clinicala stage when presentation sudden catastrophe of CNS might nocardiosis happen. interventional procedures. Therefore, the primary infection [11-14] is usually pulmonary (Figure 1) or cutaneous and if it occurs following trauma then it is a chronic granulomatous disease of It is a solitary brain abscess in immune compromised patients but in N. farcinica, multiple brain abscesses may develop due to

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Central Bringing Excellence in Open Access its more virulent nature and higher chances of resistance to the antibiotics (Figure 2). Nocardia species accounts for only 1-2% of all the cases of brain abscesses. Nocardiosis usually progresses and or temporal nocardiosis present with personality changes, behavioralover months disorders to years and with gross focal psychiatric neurological manifestations. deficits. Frontal Some cases of large nocardial cerebral abscesses or granulomas have a rapidly progressive clinical course with focal neurological

[15] depending upon the location of the brain lesions. Suddenly, thedeficits raised such intracranial as occurring pressure in the fungal may develop vasculopathy which and may strokes cause rupture of the nocardial brain abscess into the subarachnoid spaces or ventricles consequently developing purulent meningitis or ventriculitis with their typical clinical features. Neuropathology and microbiology [1-3,6] Nocardia produces multiloculated solitary or multiple brain abscesses (Figure 3). The CNS granulomas are rare in nocardiosis. Figure 3 The T1 weighted MRI showing multiple ring enhancing cerebral Meningitis infrequently coexists with parenchymal abscesses. abscesses without much surrounding edema. An atypical case of Nocardial abscess of the choroid plexus has been reported by Mogilner, et al. [16]. Involvement of cranial with yellowish green contents. Microscopy on the abscess or vertebral bones can cause osteomyelitis with secondary extradural abscesses. Micro abscesses in the CNS are surrounded structures, resembling Nocardia species. contents with methylamine silver staining shows filamentous The detailed microbiological studies on the, sputum, , biopsy tissues and the blood cultures (blood agar and LJ agar) theby dark occurrence red margins of cerebral and contain edema neutrophiles, surrounding mononuclear the lesion is cells, also reveal Nocardia notliquefactive a prominent necrosis, feature reactive or it may gliosis be all and together fibrosis. missing. In nocardiosis, Chronic consist of focally acid fast bacilli in chains (Figure 4) and the granulomatous changes when present adjacent to abscess may sensitivity, the branching test helps gram-positive in selecting aerobic the appropriate filaments show occasional giant cells. Durmaz, et al. [17], have reported a antibiotic regime. case of multiple nocardial abscesses in the cerebrum, cerebellum and the spinal cord. Different species of Nocardia may be characterized better These organisms are well seen on or methenamine mass spectrometry (MALDI-TOF MS) [18]. It is fairly a recent silver stain rather than on the H & E sections. These are acid fast by matrix-assisted laser desorption ionization-time of flight aerobic bacteria. It is easily cultured on Sabouraud’s or beef but very appealing new microbial identification technology that punctures may be needed as it is not easily isolated from the is efficient, rapid, cheap, and easy to use. It can be successfully infusion glucose agar in one to 4 week’s time. Multiple lumbar starting from subcultures on agar plates and broth media but also directlyused in clinicalfrom positive diagnostic blood laboratory cultures andfor microbial to a lesser identification extent from clinical samples such as CSF, blood, sputum, urine etc. According abscesses.Cerebrospinal The routine fluid (CSF) CSF analysis samples. reveals The only CSF mild studies pleocytosis, show raisednonspecific , abnormalities low sugar unless contents meningitis and raised coexists intrathecal with IgM the such as 16SrRNA that provide taxonomical data on a single gene and IgA synthesis. to many studies, in contrast to housekeeping genes sequencing Biopsy of the lesion usually reveals the presence of an abscess multiple components that characterize a suchat a time, as Nocardia. MALDI-TOF Molecular MS fingerprints diagnostics provide are very information helpful in aboutcases

and still evolving in its various technologies. where there is problems in identification of the Case studies In our series of six cases of cerebral nocardiosis, one patient was in coma that had presented initially with frontal sinusitis, cranial osteomyelitis, extradural abscess and bifrontal multi loculated intra-parenchymatous abscesses and then he worsened suddenly. Surgical excisions of these abscesses were performed but the patient died and no autopsy could be performed. Our second case of nocardiosis had a renal transplant and was having a pulmonary abscess. He had a multiloculated temporo-parietal cerebral abscess which was aspirated stereotactically and then Figure 2 Bilateral frontal intracerebral abscesses in nocardiosis. the patient was treated successfully initially with cephalosporins,

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Central Bringing Excellence in Open Access indicating the state of intraventricular rupture of the nocardial brain abscess [22]. The CT scans show ring enhancing intraparenchymal lesions in cases of nocardial cerebral abscesses. It demonstrates mainly hypo-attenuation lesions with contrast-enhancing peripheral rims and very little surrounding edema. Indium-111 labeled

cerebral neoplasms. leukocytes scanning may differentiate abscesses from the The diagnosis predominantly depends on the detailed microbiological and histopathological studies on the specimens of pus and the tissues obtained from the cerebral lesions usually at the craniotomy or stereotactic/ image guided burr-hole aspirates and biopsies, as detailed earlier. Treatment [3-6,8-10,17,22,23] Figure 4 Nocardia Acid Fast Gram Stain. Successful treatment of the nocardial cerebral abscesses or granulomas is achieved by the combination of most effective and then cotrimoxazole (960/480 mg QID daily) on long term anti-nocardial medications and timely guided stereotactic or drug therapy. The third case of pulmonary nocardiosis had open surgical procedures such as the drainage of the abscess. right fronto-temporal brain abscess which was micro-surgically Extensive excisional debridement of the infected cranio-cerebral excised. It was then diagnosed as nocardiosis and treated with or spinal abscesses or granulomatous tissues via craniotomy or co-trimoxazole on long term basis with good results. Two other laminectomy should be performed wherever possible. cases of brain abscesses had initially fronto-ethmoidal sinusitis which was treated with antibiotics prior to the diagnosis and Among the medications, Sulfonamides are the drug of choice then antifungal medications. Later these patients have developed (DOC). Recommended primary treatment is with intravenous frontal brain abscesses, which were aspirated stereo-tactically trimethoprim with sulfamethoxazole, 4-8 grams per day in and the diagnosis of nocardiosis was established. Aggressive divided doses for 3-4 months and then the oral preparations for a period of 8-10 months. In patients having allergy to the management of the nocardial sinusitis as well as cerebral sulfonamides, many alternative antibiotics are there such abscesses had resulted in a excellent results in these cases. One as ceftriaxone, , case of nocardiosis has typically presented with meningitis/ , amoxicillin, and , which should be ventriculitis which later progressed to hydrocephalus. He used depending upon the resultsamikacin, of the antibiotic , sensitivity clindomycin, tests. initially needed CSF diversion procedure in the form of external The third generation cephalosporins and intravenous imipenem ventricular drain and then the right ventriculo-peritoneal shunt (1 gm four times a day) are used with good improvement of was carried out. He did clinically very well. neurological conditions in substantial number of cases. In Spinal cord compression contrast to actinomycosis, the nocardiosis tends to be penicillin resistant. This is following vertebral osteomyelitis and intramedullary spinal abscess may rarely occur in nocardiosis [19-21]. Spinal The follow up treatment with prevention of recurrences are nocardiosis occurs commonly in cervical and thoracic regions. It usually develops by hematogenous spread from a pulmonary taken care with co-trimoxazole therapy (960/480mg QID daily) focus and presents as localized pain, radiculopathy and or many comatose patients or the patients with severe neurological for 6-12 months. Even with 4-8 weeks of active management, myelopathy. Intramedullary spinal cord abscess has been described although very rarely. Vertebral bodies are commonly including in their level of consciousness, disturbed mental deficits show recovery in their neurological symptomatology involved and para-spinal abscesses may be present [19-21]. dysmetria and imbalance. Many patients show a substantial Diagnosis [3,6,7-10] regressionfaculties, speechof cerebral disturbances, lesions on follow diplopia, up MRI facial brain scans. weakness, The brain MRI usually shows single or multiple cerebral ring The progress is best monitored by interval CT/MR scanning enhancing lesions (T1 weighted with gadolinium infusion) with in appropriate settings and the periodic assessments of general partial diffusion restriction. In case of brain abscess with multiple clinical state of the patient. Although most cases of spinal nocardiosis can be managed with medical therapy, the surgical decompressive procedures may be required in patients with Theloculi, cerebral a wide edema confluent surrounding heterogeneous the lesions hyper is minimalintensity or lesion may be is spinal cord and or nerve root compression. Syringomyelia may noted on FLAIR (fluid-attenuated inversion recovery) images. occur as a delayed of the treatment for nocardial are present. In cases of intraventricular rupture of nocardia brain spinal abscess [23]. Neuro-nocardiosis is still associated with absent. Mild dural thickening (Dural tail sign) and enhancement imaging may reveal a clear hyperintense component in the are better than before. The cure rate in cases of nocardial brain ventricleabscess, theand MRa nevous fluid attenuationformation inside inversion the intracerebral recovery (FLAIR) lesion abscesssignificant is about morbidity 50-70%. and mortality rates although the results

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Central Bringing Excellence in Open Access Prognosis [1-4,14,17,24] help in biological buffering of the soils and the large water Mortality with nocardial brain abscess diagnosed ante- reservoirstypical appearance by decomposing of the “molar the organicteeth”. These material bacilli to significantlyform micro- mortem is about 20-30% in immune competent patients but increases to 40% in cases of multiple abscesses and about 55% The commonly isolated companion bacteria which magnify the in immune-compromised patients. Mortality in disseminated lowmolecules pathogenic which potential are easily of takenActinomycetes up by the are growing Actinobacillus, plants. nocardiosis with severely compromised immune status may Actinomycetemcomitans, Peptostreptococcus, Fusobacteruium, approach 60-80%. An appropriate antibiotic therapy and a timely Bacteroides, Staphylococcus and . neurosurgical procedure for the abscesses and granulomas (aspiration/excision) form the basis of the essential treatment in The transmission, dissemination and co-morbid the majority of nocardiosis patients. etiological factors [3,6,29] THE CNS ACTINOMYCOSIS: BRAIN ABSCESS [1- Actinomycosis is an indolent, slowly progressive, chronic 6,25,26] infection caused by anaerobic or microaerophilic bacteria (Actinomyces israeli and Actinomyces bovis) belonging to Introduction Actinomyces. Actinomyces israeli is a normal inhabitant of the Actinomyces are one of the common bacteria habitant in mouth, colon and vagina and is not found free in nature. It soil, oral cavity, and colon producing Actinomycosis which is requires devitalized tissue to provide an anaerobic environment worldwide in distribution. Actinomycosis is a rare infection for growth. The portal of entry is the damaged mucosal in humans and is commonly seen clinically as cervico-facial lining. Actinomycosis is basically a chronic suppurative and “lumpy jaw” and less commonly, as thoraco-abdominal or pelvic granulomatous infection characterized by the multi-lobulated or actinomycosis. The males in between the third decade to the loculated abscesses containing the sulphur granules. The sulphur sixth decade of their life are affected more than the females in the granules consist of thin (less than 1µm) branching Gram positive ratio of 70% to 30 %. This rare infection occurs in the frequency of one case in 250,000 to 400,000 people especially with poor made up of linearly arranged contiguous Actinomyces bacilli. actinomycetic filaments in matted tangles which are essentially dental hygiene and low socioeconomic communities worldwide The disease has three primary forms: Cervicofacial without any racial discrimination. Widespread use of antibiotics (mandible), thoraco-abdominal (pulmonary and ileocaecal dramatically improved the prognosis with excellent results region) and pelvic. The CNS involvement occurs in 2-5% of all nowadays. cases by direct tissue invasion or hematogenous dissemination. The CNS actinomycosis is a rare disease most frequently The organGram Positive Actinomyces israeli contiguous forming cerebral abscesses and infrequently granulomatous lesions [25-27]. Actinomycosis is characterized by mixed structuresPathophysiology without difficulty. [1-6,24,25,29] connective-tissue proliferation, and the presence of Actinomyces pathognomonicsuppurative and sulfur granulomatous granules. Similar inflammatory types of reactions, granules less frequently in the lower and female have been reported in infections due to the organisms such as genital tract. These are are normal opportunistic flora of microorganisms the oral cavity always and seen co- , madurae, and Staphylococcus exist with companion bacteria (co-pathogens) which enhances aureus (). The granules are yellowish particles invasiveness of actinomycosis. These companion bacteria cause approximately 0.1-1mm in diameter. Interestingly, many bioactive metabolites of the Actinobacteria (Streptomyces spp.) devitalized tissues for the invasion of the deeper tissues by the are used in medicine such as aminoglycosides, chloramphenicol, Actinomycesa break in the and integrity result inof abscessesthe mucous and membranes granuloma and formations. result in tetracyclines, macrolide, anthracyclines, etc. Once infection is established, the host mounts an intense Types of actinomyces [1-3,6,25-28] inflammatory response (suppurative, and granulomatous), Initially, Otto Bollinger had discovered Actinomyces bovis in spreads contiguously, frequently ignoring tissue plane barriers and in long run, the fibrosis usually follows. Infection typically cattle in 1877, and shortly afterwards James Israel did A. israeli and invading surrounding tissues or the organs in continuity. in humans. In 1890, Eugen Bostroem isolated Actinomyces from a Ultimately, the infection produces draining sinus tracts. culture of grains and soil. Hematogenous dissemination to distant organs may occur at any stage of actinomycosis, whereas lymphatic dissemination is very The Actinobacteria in the phylum of Gram positive bacteria unusual. belongs to Actinomycineae [29] - family Actinomycetaceae, order , subclass and Streptomyces Cervicofacial actinomycosis is the most common type of the species, genus Actinomycetes with nearly 25 Actinomyces or infection, comprising 50-70% of reported cases. This infection “Actinomyces Actinomyces typically occurs following oral surgery or in patients with poor israeli and less commonly Actinomyces bovis are isolated but other dental hygiene. It is characterized in the initial stages by the soft- important specieslike organisms” are Actinomyces identified. gerencseriae Commonly, Actinomyces tissue swelling of the peri-mandibular or parotid area. Direct turicensis, Actinomyces radingae, and Actinomyces europaeus. spread into the adjacent tissues occurs over time, along with These non-acid fast, non-spore forming, and anaerobic-to-

development of fistulas (sinus tracts) that discharge purulent microaerophilic filamentous bacteria are forming colonies with material containing granules with yellow sulfur like appearance JSM Brain Sci 2(2): 1013 (2017) 5/10 Sharma et al. (2017) Email:

Central Bringing Excellence in Open Access (termed sulfur granules). Invasion of the cranium or the bloodstream may occur if the disease is left untreated. some microorganisms, insufficient cell lysis and/or low quantity approachesof sample material such as can 16S be rRNAproblematic gene sequencing.for efficient AMALDI-TOF study by thoraco-abdominal abscesses, intrauterine device, alcohol abuse identification and require the use of alternative identification andThe Rendu-Osler-Weber risk factors are oro-dental disease [3,6]. , paranasal sinusitis, Neuropathology [1-6,25-27,30,31] methodsBizzini et showedal. [33], that focusing 133/410 on the (32.4%) identification isolates of could 410 clinical not be isolates that could not be identified with conventional laboratory As the organisms, Actinomyces, colonize areas of mucous membrane in the body, any breach in the continuity of this ineither the BioTyperreliably identified database with for 58% MALDI-TOF. (78/133) The of the failure isolates to obtain and to a membrane (usually caused by the companion bacteria) may lead poorreliable protein identification spectral wassignals due for to the41.4% absence (55/133) of reference of the isolates. spectra to invasive actinomycotic infection. Following tissue invasion, The authors supposed that the poor spectrum quality observed Actinomycetes bacilli form tiny visible clumps called grains or sulfur granules. The Actinomycotic lesions are purulent foci bacteria such as Gram-positive bacilli and/or to fastidious growth ofcould some be isolate,due to either which the yielded difficulty only to small lyse the amount of available of some actinomycosis is characterized by the draining sinuses, extensive surrounded by dense fibroses. Therefore, clinico-pathologically, to the genera Actinomyces, Nocardia, and Streptomyces could be sulphur granules. Actinomycosis progresses contiguously across observedsample material. in this study. Difficult to identify microorganisms belonging thefibrosis, tissue pus boundaries, filled micro-abscesses with multiple containing discharging multilobulated sinus tracts (resolving and recurring) and is a refractory or a relapsing Clinical symptoms infection with short term antibiotic treatment. As stated earlier, clinically actinomycosis presents in various The most common form of the CNS actinomycosis is the forms: cervico-facial (Lumpy jaw: poor dental hygiene, oral intracerebral abscess [3,6,25-27,30,31]. The abscess is typically neoplasm, radio-osteo-necrosis), [34,35] thoracic (aspirations, poor dental hygiene), [36-38] abdominal (perforated , actinomycosis, the meninges are invaded causing epidural and mesenteric ischemic necrosis, foreign bodies) [38,39] and subdurala single thick empyemas walled associated multilobulated with lesion. cranial In osteomyelitis. cervicofacial pelvic (intra-uterine contraceptive devices) [40]. Lumpy jaw Involvement of the spine in pulmonary actinomycosis occurs as ( non-tender and woody hard), usually, occurs as a painless a result of contiguous spread of infection with the production reddish-bluish perimandibular swelling with multiple sinus of osteomyelitis and epidural abscess [32]. Microscopically, actinomycotic abscesses have central liquefactive necrosis, trismustracks draining (Figure 5). pus The with exudates h/o remittance show sulfur and granules recurrence made up with of theprogressively Actinomyces increasing bacilli. Thoracic difficulty actinomycotic in mastication abscess and intermittent presents areneutrophils, present mononuclear in the abscesses cells, with granulation multinucleated tissue, fibrosis giant cells. and Granulomasbacterial filaments. are seen Lymphocytes, in patients with plasma long standing cells and infection monocytes [1- in breathing and constitutional symptoms (fever, anorexia, 3,6,27]. lethargy,with chest ,pains, , nausea, and vomits,blood tinged loss expectoration, of body weight, difficulty etc.). Abdominal actinomycosis mainly present with constitutional In the needle aspirates and the surgical biopsies, one should symptoms but occasionally a feeling of a mass lesion in the abdomen as well. Pelvic and perineal pains with vaginal bleeding cultures are placed immediately under anaerobic conditions or discharge occur in pelvic actinomycosis. andlook incubated for the sulfurat least granules for 48 hours for or a definitivemore. The sulfur diagnosis. granules The are crushed between 2 slides, stained with 1% methylene- blue solution, and examined microscopically for the features characteristic of Actinomyces

. At low magnification, the colonies actinomyceteof the sulfur granules micro-colonies look like surrounded molar teeth by or neutrophils cauliflower and shape co- existingand at highcompanion magnification bacteria. (X100), like clumps of filamentous Gram stain shows actinomycotic micro-colonies as Gram- rods, with radially arranged, peripheral hyphae. On H & E sections, positive, long beaded, and intertwined branching filamentous chainthe basophilic reaction) filaments and Nucleic are terminating acid probes in are eosinophilic being developed clubs. The for moreCSF studies accurate tend and to rapid be normal diagnosis. or nonspecific. The serological PCR tests(polymerase have no bacteria in the routine practice. New modern technological advancesrole in the made diagnosis. it possible At times, to more there accurately are difficulties identify tothe identify micro- Figure 5 Cervico-facial actinomycosis-healed sinus tract in front of the tragus organisms such as Actinomyces i.e., molecular technologies, in the mandibulo-parotid region. MALDI-TOF-MS studies, and 16S rRNA gene sequencing. For

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Central Bringing Excellence in Open Access Although no age is immune, actinomycosis commonly while one case had an extradural granuloma following a dental occurs in middle ages with male preponderance. Usually, the extraction and one patient with cerebral abscess following orbital CNS actinomycosis develops through direct continuity of oro- actinomycosis. With appropriate antibiotics in their high doses cervico-facial disease and infrequently via hematogenous spread for a prolonged periods, and added neurosurgical management, from lungs and colon [3,6,25,41]. In cases of CNS actinomycosis, thirteen patients were either asymptomatic or mildly cerebral abscess is the most common presentation but in the symptomatic while one expired due to extensive subarachnoid patients who are repeatedly treated but have poor compliance hemorrhage. In this case no autopsy was performed. or inadequate courses of antibiotics, in them the cerebral Spinal actinomycosis results from direct extension from granulomas become main presentation. This lesion commonly pulmonary or abdominal actinomycotic foci and it involves presents with progressive symptoms and signs of raised vertebral bodies, related ribs, pedicles, laminae and spinous processes but intervertebral discs are commonly spared in to the location. There may be a single or multiple brain lesions, actinomycosis. Anterior vertebral body surfaces may show a saw abscessesintracranial or pressure granulomas. and focal Meningitis neurological is a deficits rare presentation. appropriate tooth appearance. Para-spinal abscess and pus draining sinuses Chronic meningitis in actinomycosis may occur due to the spread are common occurrences, whereas the spinal cord compression from paranasal sinuses and the middle ear cavity or mastoid sinuses. swelling of the cervical soft tissues, destruction of the occipital Acute presentation may occur due to the rupture of the boneis rare. and One posterior of our elements cases, as of mentioned the upper before, cervical had spine. marked She actinomycotic abscess in the subarachnoid spaces or in the was diagnosed with biopsy and treated effectively with long ventricle. Rarely, it may also present with acute subarachnoid term medical therapy. There was no spinal instability. The other hemorrhage with fatal outcome. patient had cervico-thoracic extradural actinomycotic granuloma which was excised twice and treated with antibiotics with good Spinal actinomycotic infection may occur from direct improvement. extension/continuity of infection in the cervical, thoracic and abdominal regions [41-44]. Spinal osteomyelitis with para-dural Laboratory and neuroimaging diagnostic studies [3- abscesses may result. The infection runs a relentless course over 6,7-10,25-27,31,32,41-43,45] many years with destruction of contiguous bones and soft tissues.

Case material present in the patients such as mild anemia, raised ESR and CRP The nonspecific hematological features of infection are Fourteen cases of CNS actinomycosis with cerebral values with leucocytosis [1-3,5-7,26-29]. High index of suspicion complications in twelve cases and spinal problems in two cases is needed in patients who have history of facial discharging sinus, were seen as evaluated by the authors in their case materials. dental extraction, appendicectomy or pulmonary actinomycotic These patients were intermittently treated with multiple infection. Involvement of jaw may show painless swelling, woody courses of antibiotics. Ten patients had cranial osteomyelitis induration and sinus tracts with intermittent pus discharges. The and intracranial granulomas (Figure 6) and in six of these cases diagnosis requires demonstration of sulfur granules (which are cerebral abscesses were associated with granulomas. One patient actually tightly clumped colonies of the causative organisms- had presented with an acute fatal subarachnoid hemorrhage Actinomyces israeli) present in the pus in the draining sinus or and two with spinal actinomycosis. In ten cases, the cranial/ in biopsy sections. The organisms grow on microaerophilic intracranial involvement was due to contiguous spread from the or anaerobic cultures. It is necessary to isolate the organisms from the clinical specimens (transported in anaerobic transport scalp, paranasal sinuses and the facial structures and in two cases thoraco-abdominal actinomycosis with the spine involvement ultra sound guided deep needle aspirates or surgical biopsy specimensdevices) taken (Figure directly 7). from the draining sinuses, or via CT or A chest radiograph may reveal a pneumonitis patch, pulmonary mass or a cavity, with pleural involvement but hardly any hilar adenopathy [31,43]. In thoracic actinomycosis, the mass lesion

chest wall [36-38,43]. It causes local destruction of the thoracic may extend across fissures or pleura, invading into the adjacent mass lesion with focal areas of decreased attenuation that vertebra, ribs or sternum. The CT scans confirm an infiltrative

Thereenhances may with be evidence contrast ofinfusion. previous This thoracotomy infiltrative ormass exploratory tends to laparotomyinvade surrounding for the diagnostic tissues without purposes significant [39]. The . needle aspirates

subjected to the microbiological and histopathological studies for taken via stereotaxy and the surgical biopsy specimens are then Figure 6 Cranial actinomycosis with intracranial granulomatous component and compressive mass effects on the left parieto-occipital lobes and the left a confirmatory diagnosis. occipital horn and the trigone of the lateral ventricle. sinusitis and cranial osteomyelitis [3,6,29]. Soap bubble Plain skull films may demonstrate paranasal or mastoid

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Central Bringing Excellence in Open Access used for non-pregnant women as it inhibits protein synthesis during bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. In penicillin resistant cases, for both the actinomycosis and the companion bacteria, the medications such as Imipenem/cilastatin, Amoxacillin/ clavulanic acid and are used. Cephalosporins (ceftriaxone, ceftazidime) are used to cover both the pathogenic actinomycetes and their companion gram negative bacteria, in moderately severe to severe infections. Actinomycotic cerebral abscess may be aspirated and intracranial granulomas excised with image guided techniques. Appropriate craniotomy or laminectomy procedures must

Penicillin may bring cure in spinal actinomycosis, however surgicalbe undertaken drainage, wherever spinal needed decompression as per urgency and stabilizationof the case.

of the optimal antibiotic therapy, the prognosis is far better in Figure 7 Gram Positive Actinomyces israeli. actinomycosisprocedures may than have that to befor undertaken true fungal whereinfections. indicated. In some Because cases, a complete resolution of the infection may be achieved by means vertebrae (the area of rarefaction at the site of active infection of surgical treatment and prolonged antibiotic therapy in higher and the area of sclerosis at the site of chronic long standing doses. infection) may be seen on the spinal x-rays. The CT brain scan Prognosis [3-6,26,29-34,36-38,45] abscess with surrounding edema. The abscess wall may be Fortunately, systemic actinomycosis is rare and moreover, usually demonstrates a solitary thick walled ring enhancing irregular or nodular. Multi-loculations with cerebral edema may its CNS involvement is a further rarity. It responds very well to be present [3,6,29-32]. Less commonly solid nodules or masses, the antibiotics especially Penicillin-G and if given in adequately granulomas (actinomycotic granuloma), are seen as slightly higher doses for a prolonged periods of time then the cure is hyper-attenuation lesion with contrast enhancement. The MRI possible and the relapses may be prevented. The availability scans with GD-DTPA enhancement show an irregularly enhancing of other alternative antibiotics (erythromycin, doxycyclin,

MRI scan reveals extensive involvement of the neighboring dura, , lincomycin and clindamycin) for the penicillin mass lesion mimicking an intracranial meningioma [3,6]. The falx and subdural spaces in cases of cranio-spinal osteomyelitis resistantsulfamethoxazole, actinomycotic imipenem, infections ceftriaxone, has greatly improved ciprofloxacin, the and epidural / subdural empyema. prognosis of all forms of actinomycosis. Surgical management Treatment [ 3-6,26,29,36-38] consists of image guided aspirations of cerebral abscesses and excision of granulomas as well as debridement of the involved Actinomyces are highly sensitive to which have tissues. At present, the clinical cure rates are high, and neither deformity nor death is common although the morbidities that the medical management should be with high doses and for revolutionized the management of Actinomycosis. It also clarified a prolonged period of time. The management basically includes in its management, which if achieved, will further lessen the a combined medical and surgical therapy including the surgical morbiditieskeep challenging and attain the higher role of overall awareness satisfactory and earlyresults. detection aspiration or excision of intracranial actinomycotic lesions. However, initially a cure should be attempted with medical CONCLUSIONS therapy with periodic assessment with neuro-imaging studies to The CNS nocardiosis and actinomycosis, although ubiquitous monitor the progress. Large doses of the drug of choice (DOC), in worldwide distribution, are rare gram positive bacterial intravenous “penicillin G” (at least 18-24 million units per day), infections with extremely low incidences. The causative bacteria, is given over a period of 3-4 months and followed by oral therapy Actinomyces, with penicillin or amoxicillin for 6-12 months period or more morphology. Their symptomatology could be insidious, variable as needed. Penicillin G interferes with synthesis of the bacterial and without usual are filamentous infective symptoms bacilli mimicking such as fever, fungi sweating, in their cell wall muco- during active multiplication, resulting in bactericidal activity against susceptible Actinomyces. diagnosis and preventing an early treatment. Nocardiosis may malaise, tiredness, toxic look etc; which result in delaying the The actinomycotic patients with penicillin allergy are treated present with the primary focus in the lungs, paranasal sinuses, with alternative antibiotics i.e., erythromycin, doxycyclin, actinomycosis initially manifest as dental, pulmonary, or and in the skin and secondarily infect the CNS; whereas, rifampicin, lincomycin and clindamycin, on long term basis with abdominal problem and then secondarily infect the CNS. sulfamethoxazole, imipenem, ceftriaxone, ciprofloxacin, hyperbaric oxygen therapy. In symptomatic CNS cases, they present mainly with the In pregnant women with penicillin hypersensitivity, progressive manifestations of a mass lesion frequently such as erythromycin is a safe alternative and is commonly cerebral abscess, and less frequently as granulomas but rarely

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6. Sharma RR, Lad SD, Desai AP, Lynch PG. Surgical Management of problems,with cerebritis paranasal and meningitis. sinus infections These manifestations and possibly may delaying mimick cerebral neoplasms, strokes, multiple sclerosis, ophthalmological Methodsfungal infections and Results, of the4th edn, Nervous 2000; System. 726-755. In Schmidek HH editor: the correct diagnosis and treatment. Apart from the routine Schmidek & Sweet’s Operative Neurosurgical Techniques, Indications, microbiological diagnostics, new modern technological advances 7. Lerner PI. Nocardiosis. Clin Infect Dis. 1996; 22: 891-903. made it possible to more accurately identify the micro-organisms 8. such as Actinomyce and Nocardia i.e., molecular technologies, et al. Nocardia farcinica brain abscess: epidemiology, pathophysiology, MALDI-TOF-MS Studies, and 16S rRNA gene sequencing andKumar literature VA, Augustine review. D, Surg Panikar Infect D, (Larchmt). Nandakumar 2014; A, Dinesh 15: 640-646. KR, Karim S, and help even in selection of the antibiotics for the bacterial 9. Lederman ER, Crum NF. A case series and focused review of nocardiosis: microorganisms. Clinical and microbiological aspects. Medicine (Baltimore). 2004; 83: The CNS nocardiosis and actinomycosis are effectively 300-313. treatable with their drug of choice, cotrimoxazole for the former 10. Palmer DL, Harvey RL, Wheeler JK. Diagnosis and therapeutic and the penicillin-G for the later. In resistant cases alternative considerations in infection. Medicine (Baltimore). medications (erythromycin, doxycyclin, sulfamethoxazole, 1974; 53: 391-401. 11. Alijani N, Mahmoudzadeh S, Hedayat YM, Geramishoar M, Jafari S. clindamycin) have very effective roles. Nocardiac or actinomycotic Multiple brain abscesses due to nocardia in an immunocompetent cerebralimipenem, abscesses ceftriaxone, may ciprofloxacin,be aspirated and rifampicin, intracranial lincomycin granulomas and patient. Arch Iran Med. 2013; 16: 192-194. excised with image guided neurosurgical techniques. Appropriate 12. A cluster of nocardial brain abscesses. Surg Neurol. 2007; 68: 43-49. wherever needed as per the urgency of the case. Kennedy KJ, Chung KH, Bowden FJ, Mews PJ, Pik JH, Fuller JW, et al. craniotomy or laminectomy procedures must be undertaken 13. Lin YJ, Yang KY, Ho JT, Lee TC, Wang HC, Su FW. Nocardial brain The mortality rates estimated for multiple abscesses due to abscess. J Clin Neurosci. 2010; 17: 250-253. Nocardia farcinica 14. Sharma RR, Pawar SJ, Ravi RR, Sausa J, Devadas RV, Athale S. A solitary abscess diagnosed ante-mortem is about 20-30% in immune primary Aspergillus Brain abscess in an immuno-competent host: CT competent patients are but significant. it increases Mortality to 40% within cases nocardial of multiple brain guided stereotaxy with an excellent outcome. Pan Arab J Neurosurg. abscesses and about 55% in immune-compromised patients. 2002; 6: 62-65. 15. 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Cite this article Sharma RR, Sharma A (2017) Cranio-Cerebral Abscesses in Nocardiosis and Actinomycosis: Assessment and Management Strategies. JSM Brain Sci 2(2): 1013.

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