Case Presentation & Review of Literature

Dated 25th March 2014

Age/sex- 32/M

Residence- triloki nath-kelonag-lahaul spiti

Date Of Admission- 22nd January 2014

Date Of Discharge- 11th February 2014

K/C/O immunocompromised state (HIV+) since last 1 year

Chief complaints - fever * 15 days headache * 15 days altered sensorium * 7 days

HOPI- fever-documented(till 102 F), a/w chills/rigors & sweating episodes, no diurnal variation, relieved with antipyretics, no h/o cough/burning micturition/altered bowel habits

headache- generalised, moderate intensity, no nausea/vomiting

altered sensorium- not recognising family members, irrelevant talks

H/O drooping of both eyelids rt.> lt.

H/O diplopia

No H/O abnormal body movements/tongue bite/ bladder or bowel incontinence/frothing from mouth

No H/O deviation of face/difficulty swallowing/nasal regurgitation/nasal twang/ weakness of any body part

No H/O any abrupt change in weight/mouth infections/prolonged diarrhea

PAST HISTORY- • K/C/O immunocompromised state for last 1 yr• No h/o DM/HTN/ATT/ART intake • No h/o blood transfusions in past PERSONAL HISTORY- • ex smoker, ex alcoholic, vegetarian• literate till 12th standard • works in a private factory• married since last 1.5 years without any child• no h/o any illicit drug abuse

FAMILY HISTORY- • non contributory• wife is not a K/C/O immunocompromised state

GPE- o conscious,o not oriented to time/place/person, o extremely agitated, o GCS E4V4M4 (12/15)o BP- 130/90 mm Hg, PR- 84/min o no P/I/Cy/Cl/LAPo Pupils b/l normal size symmetrical and non reactive to light

Examination

CNS EXAMINATION– o HMF- CNBAo Meningeal signs- negativeo Speech- normalo Cranial nerves- b/l ptosis with only abduction

movement in right eye & restricted upward gaze in left eye s/o rt. nuclear third nerve palsy

o Sensory- CNBAo Motor- moving all four limbso DTR- all present and symmetricalo Plantars- b/l flexor response

Immunocompromised state (HIV+) with pyrexia with headache with altered sensorium with right nuclear third nerve palsy

etiology- meningoencephalitis with midbrain involvement ?Tb ?fungal ?protozoal ?? bacterial

PROVISIONAL DIAGNOSIS

o RBS-81mg%

o S.Na- 132o S.K- 4.0 meq/lo S.Cl- 97

o Urea – 37o Creat -1.1 mg%

o Proteins- T 7.8 A4.6o Bilirubin- T0.6 C0.1 mg%o ALP 110o SGOT 45 IU/lo SGPT 55

Investigations

o Hb- 14 gm%o TLC-7670/mm3(N74.5% L 24.8% M0.7%)o ESR- 8mm/1st hro Platelets 156000/mm3

CXR PA view

Multiple round lesions in b/l frontal lobes, grey-white matter junction, right thalamus, right caudate nucleus and midbrain with extensive perilesional edema

NCCT Head

CSF examination cytology RBC 90, WBC 1 sugar 56 (concomitant RBS 78 mg%) proteins 60 mg% ADA 5 IU/l (normal <10) staining gram/ZN/india ink- NAD cl/s- growth of contaminants

CD4 count 21/microl

Multiple peripheral ring like and nodular enhancing lesions with perilesional edema in b/l frontal lobes, caudate, thalamus, midbrain, cerebellum, 1st possibility- cerebral toxoplasmosis

MRI Brain

Toxoplasma antibodies panel:

IgM 3.40 AU/ml (<6.00) IgG 87.00IU/ml (<7.20)

FINAL DIAGNOSIS

HIV-AIDS with cerebral toxoplasmosis

ON admissiono RT insertion and feed 200ml/4 hrlyo Foley’s catheterisationo Tab. Cotrimoxazole DS 1 tab stat and then ODo Inj. Dexamethasone 8 mg stat I/V f/b 4 mg I/V TDS

After 24-36 hrs after treatment initiation : conscious and well oriented

Within one week- b/l ptosis improved

Course & Management

Review of Literature

TOXOPLASMOSIS

Goldman’s CECIL MEDICINE 24TH EDN

MANSON’S TROPICAL DISEASES

Tachyzoite form causes a strong inflammatory response and tissue destruction and is therefore responsible for clinical manifestations . Under pressure of the immune system, tachyzoites are transformed into bradyzoites that form cysts

Both the cellular and humoral immune systems control primary infection but the cellular arm especially Th1 prevent reactivation

CD8+ T cells capable of lysing infected host cells play a major role as effector lymphocytes wheareas CD4+T cells are important to regulate immune response to T.gondii

Within 2 weeks of infection, IgG, IgM, IgA, IgE against parasite can be detected

In immunocompromised patients bradyzoites are released from cysts, transform back into tachyzoites and cause reactivation of the infection

Transmission routes:

Oral

Blood & organs

Transplacental

Clinical manifestations Clinical features(host immune status)

Signs and sympotoms

Pathology

Lymphadenitis(immunocompetent)

Absent(90% cases), rarely malaise, fever, night sweats,Hp+Spl+, LAP

Follicular hyperplasia, irregular clusters of epithelial histiocytes invading germinal centre

Toxoplasma encephalitis(immunocompromised)

Hemiparesis, personality changes, aphasia,seizures, weakness, sensory abnormalities

Multiple brain abscesses, foci of enlarging necrosis, microglial nodules

Retinochoroiditis(immunocompetent and immunocompromised)

Ocular pain, loss of VA, scotoma, photophobia

Necrotising retinitis posterior pole and inner layer(frequently U/L)

Congenital Toxoplasmosis(immunocompetent mothers)

Microcephaly, blindness, epilepsy, psychomotor or mental retardation

Necrosis of cortex and basal ganglia, hydrocephalus, periaqueductal and periventricular vasculitis

In immunocompetent- cervical LAP (MC), headache, malaise, fatigue, fever, myalgia, sore throat, abdominal pain, maculopapular rash, confusion,

RARELY-pneumonia, myocarditis, encephalopathy, pericarditis, polymyositis

lab diagnosis- USUALLY UNREMARKABLE (minimal lymphocytosis, raised ESR, nominal increase in aminotransferases, CSF analysis- raised pressure/mononuclear pleocytosis 10-50/slightly raised protein/increased gamma globin/PCR Toxoplasma DNA)

note- CSF of chronically infected individuals is normal

AIDS associated toxoplasma encephalitis results from reactivation of chronic latent infection in more than 95% of patients. In patients with AIDS seropositive for T.gondii, the risk for cerebral toxoplasmosis approaches 30%.

In pts. with TE resulting from reactivation of latent infection in the CNS , affected organs include grey and white matter of brain, retina, lungs, heart and skeletal muscles

Toxoplasmosis in immunocompromised

Incidence of TE correlates directly with prevalence of T.gondii antibodies, the degree of immunosuppression, the immunological response to ART and the use of effective prophylaxis against TE

>95% cases of TE is due to reactivation of latent infection and occurs mostly when CD4 count <100/microlitre

Cl/m: encephalopathy, meningoencephalitis, mass lesions

Cl/f: altered mental status(75%),fever(10-72%),seizures(33%), headaches(56%),focal neurological findings(60%) incl. motor deficits, cranial nerve palsies, movement disorders, dysmetria, visual field loss and aphasia

Without treatment, pts. may progress to coma in days-weeks

Most often involved areas- brainstem, basal ganglia, pituitary and corticomedullary junction

Diffuse toxoplasmic encephalitis may develop acutely and can be rapidly fatal; generalized cerebral dysfunction without focal signs is the most common manifestation, and CT scan findings are normal or reveal cerebral atrophy.

Spinal cord involvement manifests as motor or sensory disturbances of single or multiple limbs, bladder or bowel dysfunctions, or both and local pain. Patients may present with clinical findings similar to those of a spinal cord tumor. Cervical myelopathy, thoracic myelopathy, and conus medullaris syndrome have been reported.

Pulmonary toxoplasmosis (pneumonitis) due to toxoplasmosis is increasingly recognized in patients with AIDS who are not receiving appropriate anti-HIV drugs or primary prophylaxis for toxoplasmosis. The diagnosis may be confirmed by demonstrating T gondii in bronchoalveolar lavage fluid.

Pulmonary toxoplasmosis occurs mainly in patients with advanced AIDS (mean CD4+count of 40 cells/µL ±75 standard deviation) and primarily manifests as a prolonged febrile illness with cough and dyspnea. Pulmonary toxoplasmosis may be clinically indistinguishable from P.carinii pneumonia, and the mortality rate, even when treated appropriately, may be as high as 35%.

Ocular toxoplasmosis, ie, toxoplasmic retinochoroiditis, is relatively uncommon in patients with AIDS; it commonly manifests as ocular pain and loss of visual acuity. Funduscopic examination usually demonstrates necrotizing lesions, which may be multifocal or bilateral. Overlying vitreal inflammation is often present and may be extensive. The optic nerve is involved in as many as 10% of cases.

Other, uncommon manifestations of toxoplasmosis in patients with AIDS include the following:

• Panhypopituitarism and diabetes insipidus• Multiple organ involvement, with the disease manifesting as acute

respiratory failure and hemodynamic abnormalities similar to septic shock

• Syndrome of inappropriate antidiuretic hormone secretion and possibly orchitis

• Gastrointestinal system invasion of T gondii may result in abdominal pain, diarrhea, and/or ascites (due to involvement of the stomach, peritoneum, or pancreas)

• Acute hepatic failure• Musculoskeletal involvement• Parkinsonism• Focal dystonia• Hemichorea-hemiballismus

Tissue and body fluids- subinoculation into peritoneal cavity of mice; tissue biopsy

Serology- routine method of diagnosis IgG- Sabin feldman dye test, IFA test, ELISA IgM-ELISA; ISAGA IgA- double sandwich technique

molecular diagnostics- PCR; RT-PCR

DIAGNOSIS

Typically acute phase IgM appears first about 1-2 weeks after infection f/b by IgA and IgE. Generally IgM peaks at about 2 months. The time by which these Igs can no longer be detected is highly variable depending on the test employed usually about 6-9 months. IgG levels reach maximum at about 4 months then decline to a lower level over next 12-24 months but persist for decades.

The utility of the avidity test is based on the observation that Toxoplasma IgG Abs from pts with recently aquired T.gondii infection bind antigens weakly(low avidity) compared from chronically infected pts. with high avidity

Note- in IC pts. with TE indirect serologic methods widely used in immunocompetent pts. are unrelible because they fail to produce sufficient titres of antibodies.

Although incidence of TE among IC pts. directly correlates with the prevalence of anti-T.gondii antibodies, the absence of IgG antibody makes diagnosis of toxoplasmosis unlikely but not impossible. Anti-toxoplasma IgM antibodies are usually absent

Goldman CECIL MEDICINE

Presumptive clinical diagnosis of TE in AIDS patients is based on clinical presentation, history of exposure(as evidenced by positive serology), and radiological evaluation. {PV 80%}

Definitive diagnosis of CNS Toxoplasmosis requireso Compatible clinical findingso Identification of one or more mass lesions by CT,

MRI or other radiographic techniqueo Detection of T.gondii in sample.

DIAGNOSIS OF CEREBRAL TOXOPLASMOSIS

Detection of T gondii  DNA on polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) samples may facilitate the diagnosis and follow-up of toxoplasmosis in patients with AIDS. A positive PCR in brain tissue does not necessarily indicate active infection because tissue cysts persist in the brain long after acute infection. PCR in blood samples has a low sensitivity for diagnosis of toxoplasmic encephalitis in AIDS patients.

CSF findings may also include elevated protein and variable glucose and WBC counts (lymphocytic pleocytosis). The presence of Epstein-Barr virus DNA in the CSF favors the diagnosis of lymphoma.

Lumbar puncture may be contraindicated because of increased intracranial pressure, however.

For many clinicians, therefore, CNS toxoplasmosis is an empiric diagnosis that relies on clinical and radiographic improvement in response to specific anti-T gondii therapy.

In patients who fail to respond to specific therapy, brain biopsy can be used to secure a clinical sample for testing.

Indications for brain biopsy include either of the following:

• Single mass lesion and negative serologic results• No response to 14 days of empiric therapy Diagnostic yield of stereotactic biopsies increases

with the number of specimens obtained. Histologic findings include the followingLymphocytic meningitis, individual cyst-containing

lesionsAstroglial and microglial nodulesAssociated lymphocytic vasculitisDiffuse encephalitis

High-magnification photomicrograph shows a tissue cyst and tachyzoites in the brain parenchyma.

Radiographic features

When toxoplasmosis invades brain it causes acute encephalitis. Focal mass lesions of variable size are seen with central area of necrosis. Although grossly similar to an abscess , the lesion is unencapsulated and therefore is histologically classified as encephalitis rather than an abscess or granuloma. The imaging findings in toxoplasmosis are a reflection of these histopathological features

Typically cerebral toxoplasmosis manifest as multiple lesions, with a predilection for the basal ganglia and corticomedullary junction .

CT  Typically, cerebral toxoplasmosis appears as multiple

hypodense regions predominantly in the basal ganglia and at the corticomedullary junction. However, they may be seen in the posterior fossa. Size is variable, from less than 1 cm to more than 3 cm, and there may be associated mass effect.

enhancement - following administration of contrast there is nodular or ring enhancement which is typically thin and smooth 

double-dose delayed scan - may show a central filling on delayed scans

calcification - seen in treated cases; may be dot-like or thick and 'chunky'

MRI T1 - may be difficult to identify, but are typically iso intense or hypo intense  T2 -

intensity is variable, from hyper intense to iso intense hyper intense - thought to represent necrotising encephalitisiso intense - thought to represent organising abscess 

lesions are surrounded by perilesional oedema T1 C+ (Gd) - lesions often demonstrate ring enhancement or nodular

enhancement. Eccentric target sign (small central foci of enhancement within the necrotic cavity) is specific for toxoplasmosis

MR spectroscopy◦ increased lactate ◦ increased lipids◦ reduced Cho and NAA◦ Increased lipid-lactate peak is characteristic, however choline peak also

may be seen in few cases.

Transaxial contrast-enhanced computed tomography scan in a 24-year-old man with human immunodeficiency virus infection and central nervous system toxoplasmosis shows a low-attenuating mass with minor peripheral ring enhancement.

T1-weighted axial gadolinium-enhanced magnetic resonance image at the level of the basal ganglia in a 37-year-old patient with human immunodeficiency virus infection. The image shows 2 complex, ring-enhancing lesions in the basal ganglia on the right, surrounded by notable white matter edema. Additional lesions were noted elsewhere in the brain. This appearance is typical of central nervous system toxoplasmosis, which has the propensity to involve the basal ganglia

“Eccentric target sign”95% specificity;

25%sensitivity

Typically see clinical improvement in 1-2 weeks and radiological improvement in 2-3 weeks (MRI more sensitive than CT)

If no improvement- consider for stereotactic CT guided brain biopsy / PCR amplification of CSF for JC or EBV

SPECT; PET

D/D- PCNSLcerebral Tb cryptococcosis aspergillosismicrosporidiosis T.cruzimetastasis glioblastomas

Oxford american handbook of neurology

Neurological practice:an indian perspective by wadia

Manson’s tropical diseases

Treatment and Prevention

In patients in whom brain imaging shows multiple lesions, whether serologic results are negative or positive, antitoxoplasmosis therapy should be initiated.

In cases of impending herniation, an open biopsy with decompression is indicated.

Corticosteroid treatment may be warranted in cases of impending brain herniation. However, their use may complicate the interpretation of a response to antitoxoplasmosis therapy.

Standard therapy consists of pyrimethamine, sulfadiazine, and folinic acid in combination. Trimethoprim-Sulfamethoxazole (TMP-SMZ) can be used as an alternative regimen. A Cochrane data base review failed to find a significant difference between standard therapy and TMP-SMZ. Clindamycin/Atovaquone can be used in patients allergic to sulfa drugs. Effective antiretroviral therapy is equally important.

Anticonvulsants should be administered to pts. with history of seizures but they should not be administered prophylactically to all pts.

With antibiotic therapy, 74% of patients improve by day 7, and 91% improve by day 14. Imaging studies are performed every 4-6 weeks until complete resolution of the lesion or stabilization after partial resolution.

Primary therapy is given for 6 weeks, followed by long-term suppressive therapy at reduced doses, with the duration determined by response to highly active antiretroviral therapy (HAART).

Individuals who have completed initial therapy for TE should receive secondary prophylaxis indefinitely unless immune reconstitution occurs and CD4+T cell count >200/microlitre for at least 6 months occurs as a consequence of ART

Note (1)- most drugs used for the treatment of toxoplasmosis are active only against tachyzoite forms of the parasite and treatment does not eradicate infection

Note (2) pts with TE should be monitored routinely for ADR and clinical and radiological improvement

Patients who are seropositive for Toxoplasma should be started

on primary prophylaxis against CNS toxoplasmosis if their CD4+ count drops below 100 cells/μL.

The preferred prophylactic regimen is one double-strength tablet of trimethoprim-sulfamethoxazole (TMP-SMZ) daily, which also provides prophylaxis against Pneumocystis jiroveci pneumonia (PCP). The recommended alternative for patients who cannot tolerate TMP-SMZ is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP.

Primary prophylaxis can be discontinued in pts who have responded to HAART with an increase in the CD4+ counts >200 for more than 3 months

Thank you