By: Mohammad Al-Shoha, M.D.

PGY-1

~30 yo woman presents w 6 weeks of progressive weakness of his right side, along with some speech aparaxia developing for the last week, and some alteration and fluxuating level of conciousness the last 2 days.

No fever/chills/night sweats, + slight headache and slight nausea, no IVDU, no reason to have ischemic or hemorrhagic strokes (and no trauma).

Does have lupus for which she takes mycophenalateand corticosteroids (20-100 mg/day depending on symptoms/disease state). Not on any other medications.

Exam shows the neuro exam consistent with the history given, maybe some tongue fasiculations, flacidweakness of upper (3/5) and lower (2/5) extremitiyproximal and distal muscles. Reflexes seem slightly diminished on the affected side.

Initial labs show mild anemia and mildly low WBC. BMP unremarkable, CSF (obviously done after imaging) w 15 WBCs, leukocyte predominant, and normal glucose and protein.

MRI shown:

Can you make a diagnosis?

If an infection, what are the most likely types of infection?

Could this be CNS lupus? A stroke?

Can you make a diagnosis?

Probably an infection as the MRI shows ring enhancing lesions and the CSF had WBCs in this immunocompromisedman

If an infection, what are the most likely types of infection? A couple of likely etiologies of ring enhancing lesions in an

immunocompromised adult with a subacute presentation and minimal systemic signs of infection are nocardia and toxoplasmosis

Could this be CNS lupus? A stroke?

Both of these might cause the symptoms of the case, but neither would explain the MRI findings.

Should we biopsy her brain? What CSF study might clear things up?

Should we biopsy her brain? What CSF study might clear things up? A CSF toxoplasma PCR is pretty specific for

toxoplasmosis infection. CSF EBV PCR would indicate lymphoma. It would usually make sense to avoid a brain biopsy if the diagnosis can be made without it.

Here are some tables to get a nice broad differential

Clinically, they manifest as recurrent seizures, visual impairment, focal neurological deficit and raised intracranial pressure (severe headache, vomiting and papilledema).

If cerebral edema is severe, patients may develop loss of sensorium and posturing of limbs because of transtentorial brain herniation. Intractable headache, focal neurological deficits and vision loss are long-term sequelae in few of the surviving patients.

Many features of the lesion as well as clinical presentation and patient demographics need to be taken together to help narrow the differential. Helpful rules of thumb include:

enhancing wall characteristics thick and nodular favours neoplasm thin and regular favours abscess incomplete ring often opened toward the cortex favours demyelination intermediate to low T2 signal capsule favours abscess restricted diffusion of enhancing wall favours GBM or demyelination

surrounding oedema extensive oedema relative to lesion size favours abscess increased perfusion favours neoplasm (metastases or primary cerebral

malignancy)

central fluid / content restricted diffusion favours abscess

number of lesions similar sized rounded lesions at grey white matter junction favours metastases

or abscesses irregular mass with adjacent secondary lesions embedded in the same region of

'oedema' favours GBM small (<1-2cm) lesions with thin walls especially if other calcific foci are present

suggest neurocysticercosis

An aside from NEJM pictures: Chorioretinal Toxoplasmosis

Hafidi Z, Daoudi R. N Engl J Med 2014;370:361-361.

A 30-year-old man was incidentally found on funduscopic examination to have pigmented and sharply demarcated choroidal lesions involving the macular region. The lesions measured 5 mm in the right eye and less than 1 mm in the left eye (white arrows). There was no evidence of associated vitritis. This finding was consistent with scarring caused by inactive chorioretinal toxoplasmosis. The rest of the ophthalmologic examination was notable for low visual acuity in the right eye, at 6/150, associated with nystagmus; the best corrected visual acuity in the left eye was 6/24. The patient reported that he had always had poor bilateral vision and had not noted any recent visual changes. Serologic testing was positive for Toxoplasma gondiiIgG antibody (low level) and negative for IgM antibody. Such lesions are typical of acquired or congenital inactive chorioretinal toxoplasmosis. The presence of nystagmus and bilateral macular involvement are suggestive of a congenital origin.

caused by the obligate intracellular protozoan Toxoplasma gondii, which reactivates from latent disease in immune-suppressed states

The characteristic imaging pattern in toxoplasmosis lesions is a ring-enhancing lesion made up of an eccentric nodule with associated edema. In around 30% of the lesions, this enhancing nodule is found within and adjacent to the enhancing rim, enhancing wall of the lesions thinner than that observed in lymphomas

Some patients (14% to 27%) have a single disease focus.

Most lesions in toxoplasmosis occur in basal ganglia and in frontal and parietal lobes

significance of toxoplasma serology:

The vast majority of patients with toxoplasma encephalitis are seropositive for anti-toxoplasma IgG antibodies .Anti-toxoplasma IgM antibodies are usually absent; quantitative IgG antibody titers are not helpful.

CSF analysis — Cerebrospinal fluid (CSF) may have mild mononuclear pleocytosis and elevated protein in patients with TE.

Detection of T. gondii by PCR has demonstrated high specificity (96 to 100 percent) but variable sensitivity (50 to 98 percent) depending on the primers used. Treatment also affects diagnostic sensitivity. Thus, a positive PCR result establishes the diagnosis, but a negative one does not rule it out.

SPECT imaging — Thallium single photon emission computed tomography (SPECT) and positron emission tomography (PET) can be useful in distinguishing toxoplasmosis or other infections from CNS lymphoma. Lymphoma has greater thallium uptake on SPECT and greater glucose and methionine metabolism on PET than neurotoxoplasmosis or other infections

Definitive diagnosis of cerebral toxoplasmosis is made by pathologic examination of brain tissue obtained by open or stereotactic brain biopsy. Organisms are demonstrated on hematoxylin and eosin stains

A presumptive diagnosis can be made if the patient has a CD4 cell count <100/microL and:

●Is seropositive for T. gondii IgG antibody

●Has not been receiving effective prophylaxis for toxoplasma

●Brain imaging demonstrates a typical radiographic appearance (eg, multiple ring-enhancing lesions)

If these three criteria are present, there is a 90 percent probability that the diagnosis is toxoplasmosis

If all three of the above criteria are not met or no response to the treatment, biopsy or other diagnostic tests should be performed.

**TREATMENT — The initial drug regimen of choice is the combination of :

-->pyrimethamine(200 mg loading dose followed by 50 mg PO daily among patients <60 kg or 75 mg daily among patients >60 kg)

plus

-->sulfadiazine(1000 mg four times PO daily among patients <60 kg to 1500 mg four times PO daily among patients >60 kg)

plus

-->Leucovorin 10 to 25 mg PO daily

**For those patients who cannot take sulfadiazine due to intolerance or history of allergy, pyrimethamine plus clindamycin (600 mg IV or PO four times a day) is recommended.

The use of (TMP-SMX) has also been evaluated in two small studies due to its low cost and preliminary data suggesting similar efficacy to first line agents

Duration of therapy — For patients who respond, the duration of therapy is typically six weeks at the doses mentioned. Following that treatment, it is usually safe to decrease to a lower dose for secondary prophylaxis (chronic suppressive therapy).

Steroids — Adjunctive corticosteroids should be used for patients with radiographic evidence of midline shift, signs of critically elevated intracranial pressure or clinical deterioration within the first 48 hours of therapy. Dexamethasone(4 mg every six hours) is usually chosen and is generally tapered over several days.

Anticonvulsants — Anticonvulsants should be administered to patients with a history of seizures, but should not be given routinely for prophylaxis to all patients with the presumed diagnosis of TE

Common side effects of pyrimethamine include rash, nausea, and bone marrow suppression. Higher doses of leucovorin calcium, up to 50 to 100 mg daily, can be considered for management of hematologic abnormalities . Sulfadiazine use can lead to rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria.

Response to therapy — We assess for clinical improvement during the first two weeks of therapy. Clinical improvement usually precedes radiographic improvement. Thus, a careful daily neurologic examination is more important than radiographic studies in assessing the initial response to therapy. We then perform neuroimaging after two to three weeks of treatment.

WHEN TO INITIATE ANTIRETROVIRAL THERAPY in HIV pts — Antiretroviral therapy (ART) should be initiated within two to three weeks of starting treatment for toxoplasmosis .This recommendation is based upon expert opinion that takes into account the benefits of immune recovery versus the potential risk of immune reconstitution. There are no data specific to initiation of ART in patients with toxoplasmosis.

Possible regimens for secondary prophylaxis include:

Sulfadiazine(2000 to 4000 mg daily in two or four divided doses) plus Pyrimethamine (25 to 50 mg daily) is the first choice for secondary prophylaxis. Leucovorin (folinic acid 10 mg to 25 mg orally every da

For many patients, we use TMP-SMX (TMP 5 mg/kg/day - SMX 25 mg/kg/day) for secondary prophylaxis to help reduce pill burden. This regimen is not recommended in standard guidelines because of the lack of sufficient clinical trial data

Secondary prophylaxis for TE can be discontinued in asymptomatic patients who have completed initial therapy and have maintained a CD4 cell count >200 cells/microL for at least six months

-Primary CNS lymphoma is second most common cause of intracranial mass lesions in HIV infected patients. It occurs in up to 2.0% of HIV-infected patients

Predisposing factors include:-HIV/AIDS: approximately 2-6% of patients with HIV will develop PCNSL 5

-prior EBV infection-post transplantation-IgA deficiency-Wiskott-Aldrich syndrome It is opportunistic B-cell neoplasm which may express

Epstein-Barr virus antigens, is an uncommon variant of extranodal non-Hodgkin lymphoma that can involve the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease

-has a subacute presentation, with symptoms evolving over weeks.

Imaging: They are often multifocal and periventricular in location, have irregular and thick borders,there is often a single dominant radiologic site.

- Corpus callosum involvement is infrequent in primary CNS lymphoma

CSF:The CSF often reveals an elevated protein concentration and a lymphocytic predominant pleocytosis. Glucose concentration is usually normal, but may be lowered in the presence of leptomeningeal disease Epstein-Barr virus polymerase chain reaction of the cerebrospinal fluid is sensitive and specific (>90%)

-The demonstration of neoplastic lymphocytes in the CSF(occurs in only 15 percent of cases with meningeal seeding) is sufficient to confirm the diagnosis of PCL and obviates the need for a brain biopsy.

rarely cause multiple intracerebral abscesses in immunocompromised patients

The cerebrospinal fluid typically demonstrates a neutrophilic pleocytosis, hypoglycorrhachia, and elevated protein concentration, findings that are characteristic of bacterial meningitis

patients with CNS disease should be given TMP-SMX (15 mg/kg IV of the trimethoprim component per day in two to four divided doses) plus imipenem (500 mg IV every 6 hours).

In patients with CNS disease who have multiorganinvolvement, it is favorable using amikacin in addition to the above regimen

Microbiology-Streptococcus sp: 35-50%

especially S. pneumoniae

-sterile: 25%-mixed: variable, 10-90% of cases depending on source 3

-Staphylococcus aureus and epidermidis: following neurosurgery-Gram negative species more common in infants**common in immunocompromised patients with:human immunodeficiency virus infection, organ transplant recipients, intravenous drug abuse, chemotherapy for lymphoma, congenital cardiac defects or prosthetic cardiac valves and diabetes.

The direct spread of organisms from a contiguous site usually causes a single brain abscess. Primary infections that can directly spread to the cerebral cortex include :

-subacute and chronic otitis media and mastoiditis(spread to the inferior temporal lobe and cerebellum),

-frontal or ethmoid sinusitis (spread to the frontal lobes),

-and dental infection (usually spreads to the frontal lobes).

Risk factors for haematogenous spread include :

-right to left shunt congenital heart diseas pulmonary AVM and AVFs as seen in hereditary haemorrhagic telangiectasia (HHT)

-bacterial endocarditis intravenous drug usage (IVDU)

-lung infection lung abscess bronchiectasis empyema

-dental abscess

-systemic sepsis

commonly located at the gray-white matter junction

-The ring enhancement on post-contrast images is usually thin and smooth and often thinner along the medial margin

Diffusion-weighted magnetic resonance imaging (DWI) is capable of differentiating ring-enhancing lesions due to brain abscess from neoplastic lesions. Abscesses are usually hyperintense on DWI (indicating restricted diffusion, characteristic of viscous materials, such as pus), while neoplastic lesions are hypointenseor show variable hyperintensity that is lower than the intensity seen with an abscess

CSF:

the CSF pattern was variable, Rarely, the CSF formula resembles bacterial meningitis, which indicates rupture of the abscess into the ventricle

-The mainstay of treatment for cerebral abscesses is neurosurgical intervention and drainage of the collection. This can be performed either by stereotactic aspiration or craniotomy . Broad spectrum intravenous antibiotics are also needed and can later be changed to agents tailored to the specific organisms

encountered in immunocompromised patients such as those with HIV infection or after organ transplantationThe most common fungus that produces granulomatous lesions in the brain is Aspergillus,but Several other fungi also cause multiple enhancing lesions in the brain.

Neuroimaging :-reveals multiloculated thick walls with a necrotic core-Intracavitary projections seen inside an abscess cavity are considered characteristic of fungal abscesses which have been confirmed as fungal hyphae on histopathologic examination of the wall of the excised abscess. -mainly located in the brain stem, basal ganglia and cerebral cortex of the frontal, parietal occipital lobes; cerebellar and spinal locations are uncommon

recognized opportunist in advanced HIV (especially with neutropenia, high-dose steroids, chemotherapy, malignancy, or additional immune suppression)

Pulmonary disease usually precedes CNS dissemination. Sinus disease with direct extension into the orbits or CNS may occur.

Dx:- CSF : pleocytosis and moderately elevated CSF proteins are present, but CSF glucose is usually normal in CNS Aspergillosis. There are many exceptions to this picture and virtually any CSF response can occasionally be seen, including a normal spinal fluid. Organisms are rarely found in CSF. -Serial serologic tests (i.e. double diffusion counterimmuno-electrophoresis, immunofluorescence, or enzyme-linked immunosorbent assay) significantly help in arriving at a diagnosis. Immunoasssay may detect the disease early but these tests are rarely done. Treatment: Aggressive neurosurgical intervention for

surgical removal of Aspergillus abscesses, granulomas, and focally infarcted brain, correction of underlying risk factors. Amphotericin B combined with flucytosine and treatment of the source of infection should form the mainstay of the management

rarely associated with cryptococcoma, seizure, or focal deficit. The absence of a positive test for cryptococcalantigen in cerebrospinal fluid and serum suggests against this in our patient

cerebrospinal fluid (CSF) profile classically demonstrates a low white blood cell count in the CSF (eg, <50 cells/microL) with a mononuclear predominance .The CSF protein may be slightly elevated, while the glucose concentrations are commonly low .

Approximately 25 to 30 percent of patients with culture-proven cryptococcal meningoencephalitis have a normal CSF profile

20% incidence of CNS involvement in patients with AIDS (usually meningitis).

Histoplasmomas are rare and are usually multiple, small, and ring enhancing

uncommon in immunocompetent hosts, and has been reported in fewer than 5 percent of cases

CNS involvement may occur in immunocompromised patients, especially those with AIDS

** CNS infection may present as meningitis, epidural abscess, or intracranial abscesses, particularly in the cerebellum.

CNS involvement is thought to occur in 2-5% of patients with tuberculosis and up to 15% of those with AIDS related tuberculosis

-In endemic regions, tuberculomas account for as many as 50% of all intracranial masses

-Meningitis is the most common CNS manifestation, although tuberculomas are not uncommon. With CNS tuberculomas, a history of extracerebral disease is usually present (66%)

-Haematogeneous spread from the lungs or gastrointestinal tract is most common, leading to small subpial or subependymal infective foci

Numerous small tuberculomas are common in patients with miliary pulmonary tuberculosis

-Tuberculomas on contrast administration appear as nodular or ring-like enhancing lesions

-The diameter of these enhancing lesions usually ranges from 1 mm to 5 cm.

-isointense to grey-matter on T1 and T2 images with central areas of caseation

- Because of the low sensitivity of Mycobacterium tuberculosis cultures or polymerase chain reaction detection of mycobacterial DNA from cerebrospinal fluid, diagnosis of intracranial tuberculoma is often difficult, should be considered in endemic regions in both immunocompetent and immunocompromised hosts

The typical analysis of CSF from patients with CNS tuberculosis demonstrates a moderate lymphocytic pleocytosis, moderately elevated protein levels, and hypoglycorrachia (low glucose)

Neurocysticercosis is an infestation of the central nervous system with the larval cysts of the pork tapeworm (Taenia solium), when a man is paratenichost of the parasite. The infection results from ingestion of food or water contaminated with human feces containing the parasitic eggs

The embryos (oncospheres) develop from the eggs, penetrating the small intestine mucosa and entering the circulation and subsequently different tissues and organs where cysticerci, small tissue larvae, are developed. Cysticerci have specific affinity for the central nervous system, eyes and striated muscles what is accounted for high concentration of glucose or glycogen in these organs

After reaching inside the brain parenchyma, the cysticercus larva passes through several stages of evolution. progression through the 4 stages taking anywhere between 1 to 9 yearsThere are four main stages (also known as Escobar's pathological stages): Vesicular: viable parasite with intact membrane and therefore

no host reaction. Colloidal vesicular: parasite dies within 4-5 years untreated, or

earlier with treatment and the cyst fluid becomes turbid. As the membrane becomes leaky oedema surrounds the cyst. This is the most symptomatic stage.

Granular nodular: oedema decreases as the cyst retracts further; enhancement persists.

Nodular calcified: end-stage quiescent calcified cyst remnant; no oedema.

**common to many parts of the world including China, Southeast Asia, India, sub-Saharan Africa, and Latin America

It is thought that the immunologic process elicited by the release of dying parasite antigens is responsible for clinical manifestations of neurocysticercosis.

Usually, the lesions are <20 mm in diameter. Calcified eccentric scolex is often seen in a cysticercal lesion, often multiple and most often do not have extensive edema. Commonest location is the subarachnoid space over the cerebral hemispheres,others in decreasing frequency :basal cisterns, parenchyma(usually involve the grey white matter junction), ventricles

-imaging:Identification of a scolex in a cystic lesion is the only pathognomonic radiographic finding. Scolices appear as rounded or elongated bright nodules 2 to 4 mm in diameter within the cyst cavity. The scolex is usually not identifiable in calcified lesions, but occasionally may be visible on MRI. Other radiographic findings highly suggestive of neurocysticercosis include cystic lesions, enhancing lesions and parenchymal brain calcifications

CSF analysis(if done)-examination of the CSF typically demonstrates mildly elevated white cell counts with normal concentrations of glucose and protein. In the setting of active arachnoiditis or ventriculitis, however, pleocytosis with markedly elevated protein concentrations and decreased glucose concentrations may be observed

-Serology:Serologic testing is an important adjunct in cases of suspected cysticercosis when neuroimaging studies are not diagnostic. However, negative serology does not exclude the diagnosis

The test of choice for antibody detection is the enzyme-linked immunoelectrotransfer blot assay (EITB) developed by the Centers for Disease Control (also available in commercial laboratories)

The EITB assay can be performed on serum or CSF but sensitivity is usually higher with serum .It uses affinity-purified glycoprotein antigens fractionated by electrophoresis and has higher sensitivity and specificity than older ELISA tests (83 to 100 percent and close to 100 percent, respectively)

Studies of monoclonal antibody-based ELISA tests for detection of parasite antigens have demonstrated detection of circulating and CSF antigen and may be useful for both diagnosis as well as post therapeutic monitoring (parasite antigen levels typically fall by three months after successful treatment). The sensitivity and specificity of the assays is similar to EITB, but there is a closer correlation between circulating antigen detection and CT scanning results during follow-up

-Lung cancer, breast cancer and melanoma account for the majority of patients with metastasis in the brain

-CNS metastases that hemorrhage include: melanoma, renal cell carcinoma, choriocarcinoma, thyroid cancer, lung and breast cancers.

often manifest as rounded, well-circumscribed, ring-enhancing lesions of variable sizes surrounded by a variable amount of perifocal vasogenic edema. MRI typically reveals mild T1 hypointensity with T2 hyperintensity and fluid-attenuated inversion recovery hyperintensity at the site of the lesion

Metastatic lesions are typically subcortical, occurring in or near the gray matter-white matter junction, and are usually associated with severe perilesional edema. Has thick, irregular, ring-like enhancement especially when necrotic

glioblastoma multiforme frequently crosses the midline by infiltrating the white matter tracts of the corpus callosum. large in size and are often located deep in the white matter

Primary

-Primary demyelinating disorders include:

**clinically isolated syndrome (CIS) first symptomatic episode which may or may not progress to MS

**multiple sclerosis

**acute disseminated encephalomyelitis (ADEM) monophasic usually post viral acute demyelination often considered a secondary form of demyelination

**transverse myelitis

**tumefactive demyelination -also sometimes referred to as monofocalacute inflammatory demyelination (MAID), is a locally aggressive form of demyelination, usually manifesting as a solitary lesion greater than 2cm that may mimic a neoplasm on imaging, present with symptoms atypical for multiple sclerosis such as focal neurologic deficits, seizures, and/or aphasia

Infective

**progressive multifocal leukoencephalopathy (PML)-(PCR) analysis may assist in identifying the DNA of JC virus (the causative agent of PML)

**HIV encephalitis / HIV dementia complex / HIV associated myelopathy

**progressive rubella panencephalitis

Toxic

**central pontine myelinolysis (CPM)

**posterior reversible encephalopathy syndrome (PRES): related to hypertension predominantly

**chemotherapy

Metabolic / genetic

**leukodystrophies adrenoleukodystrophy Krabbe leukodystrophy metachromatic leukodystrophy

Ischaemia

**deep white matter ischaemia

**radiotherapy changes

-Multiple enhancing ring lesions are encountered in several acute demyelinating disorders

-Presence of an open ring or incomplete ring lesion helps in differentiating demyelinating lesions from large brain tumors or infective lesions like brain abscess

-Patients with atypical ring-enhancing lesions and mass effect usually undergo brain biopsy to establish the diagnosis

-Otherwise, biopsy of these lesions is not indicated because conservative medical treatment with corticosteroids results in a favorable outcome in most of the cases.

Toxoplasmosis needs to be on the top of your DDx list in all immunocompromised patients who present with multiple ring-enhancing lesions even those who are HIV negative

Consider fungal abscesses ,Nocardia, pyogenic abscesses, lymphomas in your DDx

Close clinical monitoring followed by radiological monitoring is important in pts with toxoplasmosis

Toxoplasma PCR in the CSF is diagnostic and eliminates the need for brain biopsy

Thanks

Questions?