Cryptococcal Meningitis and a New Diagnosis of AIDS

Today, we presented an interesting case of a young man with no past medical history who presented with two weeks of progressive headache and fever, now with nausea, vomiting, and an episode of transient blurred vision. CSF revealed an elevated white blood cell count with lymphocytic predominance, low glucose, and elevated protein. Serum and CSF CrAg subsequently came back positive and fungal blood cultures showed Cryptococcus Neoformans.

Illness script for Crypto Meningitis:
Epi: AIDS patients with CD4<100
Symptoms: Indolent onset 1-2 weeks for fever, malaise, and headache. Can develop meningeal signs, altered level of consciousness, and focal neuro deficits. Disseminated disease can include pulmonary symptoms and skin findings resembling molluscum contagiosum.
Diagnosis: Serum and CSF CrAg with 93-100% sensitivity and 93-98% specificity. Crypto can be isolated on India Ink stain of CSF 60-80% patients.
Treatment: Induction with 2 weeks of IV amphotericin B and PO flucytosine, consolidation for 8 weeks with high dose fluconazole, and maintenance for one year with low-dose fluconazole. Serial LPs for ICP control. Start ART 2-10 weeks after starting antifungal treatment (delayed due to risk of IRIS).

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The Ophthalmologist’s Pulse Examination That Identified a Vasculitis!

Today we discussed an impressive diagnostic mystery of a young woman with chronic neck pain and paresthesias who was later found to have a diminished ipsilateral pulse and a SBP of > 60 points in the affected arm compared to the contralateral arm!

The case highlighted a few, highly important points – first – that the pulse examination is paramount in the patient with paresthesias of an extremity.

A broad differential for diminished/absent radial pulse includes atherosclerosis (i.e PAD), embolism, vasculitis (i.e GCA and TA, less commonly Beurger Disease), anatomic (dissection, thoracic outlet obstruction, thrombosed aneurysm) and iatrogenic (i.e post ABG, vasopressors). When you notice unequal pulses in a patient with symptoms relating to that extremity, you must treat this as an emergency!

We then reviewed the distinguishing characteristics of GCA and TA

GCAvsTA.GIF

The key takeaway to remember is that TA is a chronic disease, filled with relapses and therefore these patients must be diligent about their immunosuppression, which in some cases may be lifelong at very low doses.

For those of you who are still here, a historical treat is your reward. At the 12th Annual Meeting of the Japan Ophthalmology Society held in 1908 in Fukuoka, the young Dr. Mikito Takayasu presented a curious case of vascular malformations of the eye. Two of his colleagues, Drs. Katsutomo Onishi and Tsurukichi Kagoshima also presented similar findings, but noted absence of pulses as well. The findings are impressive, but even more impressive is a subspecialist examining the entire body in a patient they were concerned about, a truly admirable – but increasingly uncommon – practice!

Sexually Transmitted Pharyngitis

Today’s case, brought to us by Dr. Tuan Nguyen, was a middle-aged woman who presented with sore throat and globus sensation, which persisted for >6 weeks before she received a tonsilar biopsy that showed Treponema pallidum, consistent with secondary syphilis.

We went over a strategy of evaluation of the adult patient with acute pharyngitis. First, we ruled out any emergency by evaluating for airway compromise (respiratory distress, tripoding, “sniffing,” stridor), signs of epiglottitis or deep neck space infection (muffled/hot potato voice, drooling, bulging of the structures of the pharynx or palate, torticollis, neck pain/stiffness/swelling, trismus), or sepsis. We then evaluated for the likelihood of Group A strep infection with the Centor criteria. If left untreated, group A strep pharyngitis can lead to rheumatic fever, rheumatic heart disease, glomerulonephritis, and abscess. Then, we took a detailed sexual history to risk stratify the patient for acute HIV, gonococcal pharyngitis, and syphillis.

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anti-HUH-Vasculitis?

Today we presented a very interesting case of anti-MPO vasculitis with renal biopsy confirming a pauci-immune necrotizing, crescenteric glomerulonephritis.

We first reviewed the common features of small-vessel ANCA associated vasculitides [AAV] -granulomatosis with polyangiitis; microscopic polyangiitis; eosinophilic granulomatosis with polyangiitis:

Common Systemic Signs and Symptoms– fevers, weight loss, arthralgias, malaise

  • Common Organ-Specific Manifestations
    • Kidney
      • Hematuria, proteinuria, AKI caused by GN
    • Skin
      • Purpura caused by leukocytoclasic angiitis in dermal venues and atertioles
    • Abdominal Pain and Fecal Occult Blood
      • From mucosal and bowel wall infarcts
    • Mononeuritis Multiplex from arteritis in peripheral nerves
    • Necrotizing sinusitis from upper respiratory tract mucosal angiitis
    • Pulmonary hemorrhage from alveolar capillaritis
  • Unique Organ-Specific Manifestations
    • GPA has necrotizing granulomatous inflammation seen most commonly in the respiratory tract
    • eGPA has blood eosinophilia and a history of asthma

Classification Systems

We reviewed that renal biopsy is not generally able to distinguish between the various AAVs, but rather will only be ‘pauci-immune’. The diagnosis, like all of rheumatology, truly is a beautiful integration of clinical, serological, and histological.

The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides clarified nomenclature for us and several important aspects of care has emerged from it.

Serologies in AAV

We know that vascular inflammation is cased by activated neutrophils and monocytes because of ANCAs. These ANCAs bind to a variety of antigens, most notably proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA). PR3 is tightly linked to C-ANCA and MPO to P-ANCA. In relation to our traditional clinicopathological (CPC) diagnoses of MPA, GPA and eGPA, we note the following:

Pr3mpo.png

Key takeaways are that not all “MPA, GPA and EGPA” is ANCA+, and when it is, the pattern of antigen-antibody complex is not specific! In other words, in a patient with PR3-ANCA, 75% of the time their CPC diagnosis is GPA but 40% of the time it is MPA. Putting aside the CPC diagnosis for a moment, we see that there are consistent, specific associations between PR3-ANCA/MPO-ANCA and certain clinical manifestations. For example, there is worse renal survival in MPO-ANCA patients and PR3-ANCA has consistently been shown to have a higher relapse rate and mortality rate compared to MPO-ANCA. For now, both systems of identification are useful (a serotype and CPC diagnosis) and in the future, I wonder if treatment will differ between the two. For now, regardless of the serotype of CPC diagnosis of MPA or GPA, the treatment is the same!

Treatment of MPA/GPA (eGPA tx is slightly different)

Induction

  • High dose steroids and either cyclophosphamide OR Rituximab (decision is complex and based on side effect profile i.e Rituximab in patients with concerns fertility or alopecia or if previously been on cyclophosphamide)
  • Indications for plasmapheresis include
    • Evidence of pulmonary hemorrhage (some say all, some say those who did not respond quickly to steroids)
    • Rapidly deteriorating kidney function or severe kidney dysfunction
    • Patients who have a concomitantly positive anti-GBM

Maintenance

  • Approx 80% of patients enter remission with induction therapy, but relapses are common (especially with PR3-ANCA serotype and lung or URT disease
  • Either azathioprine, mycophenolate or rituximab
  • Optimal duration not well-established, some say 12 months after remission is attained, followed by a gradual reduction

Source: National Kidney Foundation’s Primer on Kidney Diseases 7th ed, Gilbert & Weiner, 2018

UpToDate- https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-initial-immunosuppressive-therapy?

DRESS Syndrome (or DIHS)

Today Dr. Kali Xu presented a riveting case of a middle-aged man with a history of gout on allopurinol who presented with a worsening, diffuse maculopapular rash with odynophagia, dysuria, and pain on defecation with eosinophilia, elevated ALT, and AKI.

Given the mucus membrane involvement, multiorgan dysfunction, diffuse rash, and recent allopurinol initiation, the group astutely narrowed the differential diagnosis to DRESS vs SJS/TEN, which was the same differential of the dermatology team came up with.

The following is a useful table we created when deciding between these two similar diagnoses.

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Other useful clinical pearls from today’s noon report:

  • The most common triggers for DRESS: anti-epileptics and allopurinol
  • When dealing with anti-epileptic induced DRESS, many experts use valproic acid for seizure disorder treatment because it is least likely to cause DRESS
  • There is a trend toward calling DRESS syndrome DIHS (drug-induced hypersensitivity syndrome)
  • DRESS can involve any organ including liver, kidney, lungs, heart, GI, pancreas, thyroid, brain, muscles, nerves, and eyes
  • Treatment for DRESS consists of a long steroid taper, which usually required prophylaxis for osteoporosis and steroid-induced peptic ulcers with calcium-vitamin D supplementation and PPI
  • Thyroid function should be monitored 2-3 months after acute presentation because autoimmune thyroiditis can be a late presenting sequelae of DRESS

A case of psychosis with lymphocytic pleocytosis in CSF… Anti-NMDA Receptor Encephalitis!

Today we discussed a very interesting case of a young female who presented with 3 months of progressive behavioral disturbances, hallucinations, headache, insomnia, and a seizure. In young females with progressive symptoms and seizures, anti-NMDA receptor encephalitis is an important diagnostic consideration, although it is quite rare.

Illness Script for NMDA encephalitis:

  • occurs in young females with ovarian teratomas, but can be associated with other tumors as well and is sometimes seen in men and children
  • proposed association with a history of HSV encephalitis (in one study 20-30% of HSV encephalitis patients who didn’t have anti-NMDAR antibodies during their episode of encephalitis developed them later)
  • Clinical presentation: headache, fever, viral-like prodrome followed by multistage progressive symptoms:
    • psychiatric manifestations: anxiety, agitation, bizarre behavior, hallucinations, delusions, disorganized thinking
    • insomnia
    • memory deficits
    • language dysfunction: diminished language output, mutism, echolalia
    • seizures
    • decreased level of consciousness, stupor with catatonic features
    • dyskinesias: orofacial, choreoathetoid movements, dystonia, rigidity, opisthotonic postures
    • autonomic instability: hyperthermia, fluctuations of BP, tachycardia, bradycardia, cardiac pauses, hypoventilation
  • LP: can be initially negative or have lymphocytic pleocytosis or oligoclonal bands
  • EEG: Can have infrequent epileptiform activity, but frequently slow, disordganized activity that doesn’t correlate with patient’s abnormal movements
    • Unique pattern associated with prolonged illness: extreme delta brush
  • MRI: Usually normal, but can have transient FLAIR abnormalities
  • Diagnosis: CSF anti-GluN1 antibodies + clinical symptoms, abnormal EEG + oligoclonal bands, and reasonable exclusion of other disorders
  • Treatment:
    • Tumor resection when possible
    • Methylprednisolone 1g IV daily x5d
    • IVIG 400mg/kg IV daily x5d OR plasma exchange
    • If sypmtoms very severe, consider Rituximab

Acute Cholangitis without a Gallbladder

Today, Dr. Nakache presented a case of a 63yoF with a history of cirrhosis and cholecystectomy who presented with RUQ pain and sepsis with EColi bacteremia, found to have acute cholangitis.

Causes of Acute Cholangitis: Stones, strictures, malignancy, stent occlusion, s/p ERCP, postoperative (Whipple, gastric bypass, etc), or extrinsic compression (Lemme’s syndrome, acute pancreatitis, Mirizzi syndrome), parasites (liver flukes or ascaris)

Symptoms/signs: 

Charcot’s triad: Fever, jaundice, abdominal pain (only 50-75% have this triad)

Reynold’s pentad for severe cholangitis: Charcot’s triad + hypotension and AMS

Complications: septic shock, hepatic abscess, multiple organ dysfunction

Labs: Leukocytosis/evidence of infection, Cholestatic LFTs, although can also get transaminitis if hepatocyte necrosis (high 2000s, consider liver abscess)

Diagnosis:

Must meet all criteria:

  1. Evidence of systemic inflammation: Fever, shaking chills, leukocytosis, elevated CRP
  2. Evidence of cholestasis (Tbili >= 2, elevated LFTs 1.5x ULN)
  3. Imaging with biliary dilation OR evidence of cause (stones, stricture, etc.

Choice of Imaging:

Start with abd US. If negative but still very high clinical suspicion, get abd CT. If negative, but still very high clinical suspicion, get MRCP. These tests get more expensive, more time consuming, and more sensitive as you go down the list.

Caveat #1: If the patient’s is s/p cholecystectomy, abdominal ultrasound may be too nonspecific due to normal postoperative biliary dilation. Visualization of the distal CBD is also particularly poor on ultrasound.

Treatment:

  1. Supportive care (fluids, electrolyte repletion, analgesia)
  2. Antibiotics
  3. Biliary drainage via ERCP, which is successful 90-95% of cases
  4. Address the cause (consider cholecystectomy if 2/2 stones, consider stenting if due to malignancy)

Antibiotic treatment:

If infection is community acquired without risk factors for antibiotic resistance, use one of the following regimens:

– Zosyn

– Cephalosporin + Flagyl

– Cipro or Levofloxacin + Flagyl

If the patient shows signs of end-organ damage, is in septic shock, OR there are risk factors for antibiotic resistance (recent travel to Asia, Africa, or Middle East, known colonization with antibiotic resistant organisms, or healthcare-acquired infection), use one of the following regimens:

– Zosyn

– Carbapenem: Meropenem or Imipenem + cilastatin or Doripenem

– Cefepime or ceftazidime + Flagyl

Duration of Therapy:

Continue antibiotics until 4-5 days after source control.

Timing of ERCP:

70-80% of cholangitis patients respond to initial therapy and ERCP can be done nonemergently within 24-48 hours.

If they shows signs of end organ damage, are in septic shock, or do not respond to 24 hours of antimicrobial therapy and supportive care, they should get ERCP emergently within 24 hours.