ALS Presenting as Hypercarbic Respiratory Failure

Thanks to Dr. Mayo for her presentation today of hypercarbic respiratory failure in an elderly male who was later diagnosed with amyotrophic lateral sclerosis (ALS).

One way to think about the elimination of carbon dioxide is:

  • "won't breath" - CNS
  • "can't breath" - PNS, respiratory muscles, chest wall, pleura, upper airway
  • "can't breath enough" - lungs

This allowed us to think through some common causes.

  • Decreased central drive - sedative medications, stroke, OSA
  • Decreased respiratory or thoracic cage function - spinal cord injury, ALS, Guillain-Barre, phrenic nerve injury, Myasthenia Gravis, Lambert Eaton, tetanus, organophosphate poisoning, neuromuscular blockade, metabolic disorders (low Phos, Mg; hyper-hypothyroidism)
  • Increased dead space - PE, severe pulmonary vascular disease, dynamic hyperinflation (COPD, severe asthma), end stage interstitial lung disease
  • Increase CO2 production - fever, thyrotoxicosis, increased catabolism, metabolic acidosis
  • Multifactorial - vocal cord paralysis, severe laryngea/tracheal disorders, foreign body aspiration,obstructive goiter
pft_primer_fig2.gif

In this instance, pulmonary function tests (PFTs) and maximal inspiratory/expiratory pressures (MIPs and MEPS respectively) were key. Remember that neuromuscular disorders such as ALS demonstrate a predominately restrictive pattern on PFTs which means that patients may have a normal FEV1 and FEV1/FVC ratio. After diagnosis, regular spirometry (generally accepted to be every 3 months after diagnosis) is important to monitor progression. A recent review article highlights that two large trials (EMPOWER, BENEFIT-ALS) and the ALS trial database (PRO-ACT) found that the rate of decline in FVC predicts the liklihood of death. Another recent study showed that twitch trans-diaphragmatic pressure is the most powerful biomarker for mortality. But, that sniff nasal inspiratory pressure (SNIP) is an excellent correlate. And that a VC within a normal range suggests a good prognosis. Ultimately, there is no one single test which predicts all.

Cutaneous Polyarteriitis Nodosa

 The histologic classification of cutaneous vasculitis. Imaged referenced from  Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology; 56:3-23.  

The histologic classification of cutaneous vasculitis. Imaged referenced from Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology; 56:3-23. 

Thanks to Dr. Fleming for presenting an interesting case of cutaneous polyarteriitis nodosa which started as distal peripheral neuropathy.

Cutaneous PAN is a rare form of PAN. There is a slight female predominance (1:1.7) with an average age of diagnosis 43.5years. The etiology is generally unknown. However, it may reflect underlying disease, infection of medication use. Individuals with CPAN should be evaluated for: antecedent Group A beta hemolytic strep infection (check an ASO), hepatitis B, hepatitis C, parvovirus, mycobacterium TB, IBD, minocyline use.

Diagnosis requires pathologic correlation with clinical findings. Histologically there is small/medium artery vasculitis clinically presenting as tender subcutaneous nodules on the lower extremities, often with livedo reticularious and cutaneous ulceration. There are no specific serologic tests.

CPAN is described as a chronic, relapsing and remitting course. Treatment is less aggressive than PAN. Mild cases responds to NSAIDs and topical corticosteroids. More refractory cases require corticosteroids and immunomodulators indlucing hydroxychloroquine, azathioprine, dapsone, cyclophosphamide, methotrexate and IVIG. The prognosis is good without any known mortality for CPAN itself. However, there is a potential for progression to PAN. One study notes 2 out of 20 patients with CPAN developed PAN after 18 and 19 years of follow-up.

For additional reading, please refer to Morgan AJ et.al. Review: Cutaneous polyarteritis nodosa. Int J Dermatol. 2010 Jul; 49(7):750-6.

 Types of cutaneous vasculitis. Table created in reference to UpToDate resource entitiled "Types of cutaneous vasculitis" 

Types of cutaneous vasculitis. Table created in reference to UpToDate resource entitiled "Types of cutaneous vasculitis" 

HIT

Dr. Hill presented a case today of heparin induced thrombocytopenia (aka HIT). His PICO question looked at whether patients receiving therapeutic heparin compared to prophylactic, subcutaneous heparin had higher incidence of HIT. An article in CHEST 2007 looked to determine the overal incidence of HIT in a tertiary care center based on retrospective review. It found an overal incidence of 0.2% with 0.76% incidence receiving therapeutic heparin compared to less than 0.1% incidence receiving prophylactic dosing. Similarly, in a 2011 article in British Journal of Hematology found that full dose anticoagulation with unfractionated heparin had a RR 3.66 (CI 1.98-6.75) compared to prophylactic dosing.

Generally, the teaching points from the case presentation were:

  • thrombosis is the presenting finding in up to 25% of patients with HIT
  • venous and arterial thrombosis occurred in 61% and 14% respectively in one restrospective review in the American Journal of Medicine.
  • the 4T score is useful to establish pre-test probability
 4T scoring system as described in  CHEST 2013

4T scoring system as described in CHEST 2013

Additional review of HIT can be found in the CHEST review from 2012.


Dr. Deloughery (Hematology/Oncology) weighs in with a couple of more key articles on HIT:

1) This new review is good by two of the masters of HIT

2) IVIG article is based on two OHSU cases

3) Former resident along with Shatzel did a review of DOAC for HIT that is widely quoted

Also at OHSU cost of UFH = that of Lovenox

Shoulder Pain + Brachial Plexus Review

Thanks to Dr. Brooke for presenting a case of shoulder pain with C6/C7 weakness and lack of sensation to the thumb which prompted the dreaded review of the brachial plexus, nerve roots and dermatomes.

The most commonly affected nerve root is C7 (~70%) followed by C6 (~20%). Sometimes it may not be clear that the problem is at the nerve root itself. Occasionally one can be tricked to by peripheral neuropathies mimicking nerve root compression. Below are a few distinguishing factors.

Provocative maneuvers are also helpful tools to distinguish the location of the lesion and to assess other etiologies on the differential. 

  • Spurling test: highly specific and sensitive for cervical radiculopathy; passive movement of patient's next into lateral flexion and extension followed by gentle downward axial compression, + test reproduces radicular symptoms
  • Shoulder abduction test: highly specific; place the palm of the affected side on the patient's head; + test results in relief of radicular symptoms 
  • Upper limb tension test: most sensitive to rule out radiculopathy; with the patient supine and the shoulder neutral and the elbow and wrist flexed, the shoulder is then abducted 90 degrees and the elbow and fingers extended with wrist supination as the patient's neck moves to the contralateral side; + test reproduces radicular symptoms
  • Tinel sign: low sensitivity, moderate specificity for carpal tunnel syndrome; pain or parasthesias in a median nerve distribution with tapping the volar wrist over the carpal ligament
  • Phalen maneuver: moderate sensitivity and specificity for carpal tunnel syndrome; pain or parasthesias in the a median nerve distribution after 60 seconds of wrist flexion at 90 degrees with full elbow extension (for Carpal Tunnel review, see the associated AAFP article). 
  • Adson's test: for thoracic outlet obstruction; with inspiration, chin elevation and head rotation to the affected side a + test alters or obliterates the radial pulse 

For additional review of provocative c-spine testing, refer to the Pain Physician article from 2003. 

 

Cardiac Amyloidosis

Thanks Dr. Ellis for presenting a case of cardiac amyloidosis. For those who missed it, the case was of a 70 y/o iron man participant who developed exercise-induced fatigue. His labs were unremarkable, and his EKG was notable for new TWIs in the anterolateral leads. Echo showed left atrial enlargement and RVSP of 41. His left heart cath was clean but cardiopulmonary exercise testing suggested chronotropic incompetence, leading to pacemaker placement. Despite multiple adjustments to the pacer, he continued to have symptoms and sought further counsel. In the end, cardiac MRI showed late gadolinium enhancement, and subsequent endomyocardial biopsy revealed cardiac amyloid.

Key points:

  • Classic presentation for cardiac amyloidosis is HFpEF
  • Key physical exam findings may include periorbital bruising and macroglossia
 Left: small periorbital bruise; Right: macroglossia  Images courtesy of JACC 2016 article entitled  AL (light-chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy

Left: small periorbital bruise; Right: macroglossia

Images courtesy of JACC 2016 article entitled AL (light-chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy

  • Approximately 50% of patients will have low voltage on ECG
  • Cardiac MRI shows late gadolinioum enhancement over the entire subendocardial circumference
 MR to aid in diagnosis of cardiac amyloid and estimate or amyloid burden.  Images courtesy of JACC 2016 article entitled  AL (light-chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy

MR to aid in diagnosis of cardiac amyloid and estimate or amyloid burden.

Images courtesy of JACC 2016 article entitled AL (light-chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy

  • Definitive diagnosis requires endomyocardial biopsy with Congo red staining but consider less invasive non-cardiac biopsy before obtaining endomyocardial biopsy

Acute Hepatitis B

Thanks to Dr. Xu for presenting a case of acute hepatitis B infection. This allowed for several clinical pearls and some review. First, Hepatitis B is decreasing in the USA. And in 2016, there were only 20 reported cases in Oregon. The decrease is likely as a result of vaccinations. Note, there is a new FDA approved two-dose HBV vaccination available called HEPLISAV-B (click here to read more about ). Remember that transmission is via blood and body fluid exposure. Therefore, make sure to ask about their practices and test partners/close contacts. For additional review of both clinical course and epidemiology, please refer to the CDC. A few other points from today:

1) Differential Diagnosis of Transaminases in the 1000s

  • ischemic: Budd Chiari (look for other evidence of end organ damage)
  • acute viral (HAV, HBV, etc)
  • drugs/toxins (often Tyelnol)
  • other less common etiologies include: exacerbation of autoimmune hepatitis and HELLP syndrome

2) Hepatitis B Typical Serologic Course

 Courtesy of the  CDC

Courtesy of the CDC

 Courtesy of the  CDC

Courtesy of the CDC

3) Treatment: in a non-cirrhotic patient with acute HBV infection, a 2017 Cochrane Review showed that there is poor quality evidence to suggest that treatment vs. no treatment decreased the rate of progression to chronic infection. Thus, expectant managment is fine in most immunocompetent adults. However, if treatment is chosen, it may be useful to avoid lamivudine which has a higher rate of progression to chronic HBV than did the groups treated either with entecavir or placebo. Of note, the exclusion criteria were liver diease, liver failure, drug/alcohol abuse and immunosuppression. So, the case discussed would have been excluded.

Amyloidosis and MM

Dr. Myers presented a case today of abdominal fullness and LE edema ultimately found to have endomyocardial biopsy proven AL amyloidosis and multiple myeloma. This case prompted further investigation into the cardiac considerations when contemplating therapy for multiple myeloma (MM). This topic is discussed in a 2016 article in the American College of Cardiology along with a highlight of new MM therapies that do not have a strong cardiac signal. They conclude that as MM treatments continue to evolve (chimeric antigen T-cell therapy, bromodomain inhibitors, etc) that the field also needs to improve managment of cardiovascular risks and prevention strategies especially in light of the increased cardiovascular risk in this cohort at baseline.

 Review of CV risk factors in patients with MM from a  2016 ACC  article. 

Review of CV risk factors in patients with MM from a 2016 ACC article. 

AIN after Combo Immune-Checkpoint Inhibitors

 A and B: urine sediment with granular cast (A) and WBC cast (B) suggestive of AIN. C: non-pruritis morbilliform erythematous rash all of which may be seen in a patient treated with nivolumab and ipilimumab for metastatic melanoma. Please refer to the article in  Clinic Kidney Journal  for more information. 

A and B: urine sediment with granular cast (A) and WBC cast (B) suggestive of AIN. C: non-pruritis morbilliform erythematous rash all of which may be seen in a patient treated with nivolumab and ipilimumab for metastatic melanoma. Please refer to the article in Clinic Kidney Journal for more information. 

Today's case highlights the ever changing frontier of medicine with the use of immunotherapies. Immune-checkpoint inhibitors are being used more and more frequently as anti-cancer therapy. And it has become common to look for the emergence of an autoimmune phenotype (the "-itis": hypophysitis, pneumonitis, colitis, hepatitis, etc). Dr. Oldham shared a case of acute interstitial nephritis (AIN) in the setting of combination immunotherapy with nivolumab and ipilimumab for metastatic melanoma.

Recall that nivolumab and pembrolizumab are anti-PD-1 therapies and, ipilimumab is an anti-CTA-4 therapy. On these therapies, immune-related adverse events occur in up to 60% of patients per reports. Often they are mild to moderate. However, with the utilization of combination immunotherapies, additional adverse events are being reported and at increasing rates. One recent study of nivolumab and ipilimumab combination therapy for melanoma in NJEM reported higher adverse events for dual therapy (55%) compared to either therapy alone (16.3% for nivolumab and 27.3% for ipilimumab). Notably however, severe renal impairment was rare. Yet, in the last two years there are several case reports of AIN associated with combination immunotherapies.

 Figure from  NJEM  article

Figure from NJEM article

One group from Brigham and Women speculates that this may be synergy between the two blocked pathways allowing for untethered cytotoxic effects.

While more information is necessary, this adds to the potential side effect profile of anti-cancer immunotherapies. And, it highlights the necessary vigilience we must have in order to properly diagnose and treat these individuals.