Monday, 9 February 2009

Answer To January's Case

Dear Bloggers

Thank you for waiting for the answer to January's case. I was informed that it might have been a bit too difficult. However, residents still need to be able to understand all the problems in any patient case in order to construct a logical plan of further investigations and / or treatment.

Although this patient had many problems, it is not a rare occurrence for patients of advanced age to accrue disease which muddies the water when trying to make a diagnosis for a main problem; hence Ockham vs Hickham (see below). This is where clinical acumen, logical testing and using the mental probability assessment of common things being common and uncommon things being uncommon comes into play.

At the end of the day, it is sometimes necessary to obtain a biopsy to get the diagnosis - as Prof Lawrence Tierney says "Tissue is the issue". Let's see whether that was necessary in this case.

Professor Masami Matsumura who is well known to this blog for his excellence in problem solving has again astounded me with his opinion on this very difficult case.

We have to consider the contrast between Occam’s Razor and Hickham’s Dictum because this patient is a high aged woman. Did she have SINGLE disease or MULTIPLE diseases? She had multiple processes as follows;
1. Chronic inflammatory condition including neoplastic disease
2. Neuropathy
3. Masses in mouth and submucosa in upper GI tract
4. Heart failure
5. Emphysema

It is impossible to interpret ALL problems within SINGLE disorder. Firstly, I would focus on the chronic inflammatory condition and neuropathy.

Questions 1) Please make a full list of ALL the patient's problems and make assessments according to diagnostic grouping.

I listed problems as follows;
#1 Fever

#2 Weight Loss
#3 Sweats (suspect dehydration)

#4 Fatigue

#5 Normocytic anemia
#6 High ESR

#7 Foot numbness (L4, 5, and S1)

#8 Leg Pain (disappeared)

#9 Unusual scalp feeling

#10 Shoulder Pain (for several years)
#11 Fixed 'shotty' nodes in the groins

#12 Mass in oral cavity
#13 Submucosal mass in upper GI tract
#14 Dyspnea

#15 Tachypnea

#16 Hypoxia
#17 Tachycardia, Atrial Fibrillation
#18 Effusions

#19 Wet early crackles

#20 Cardiomegaly

#21 Pitting edema > 40 seconds
#22 Hypertension

#23 Quinke's sign

#24 ex-smoker
#25 Hyper-expanded chest
#26 Fibrotic change in the lung

#27 Elevated ALP
#28 Impaired Glucose Tolerance
#29 Insomnia

#30 Cataracts
*I can’t interpret following finding correctly; Trachea .. with two-fingers appliable to the suprasternal notch I guess this finding was caused by emphysema. (correct - tracheal tug)


Chronic inflammatory condition including infection, neoplastic, or autoimmune disease should be considered from #1 Fever, #2 Weight Loss, #3 Sweats, #4 Fatigue, #5 Normocytic anemia, and #6 High ESR. This patient disclosed B symptom. Vasculitides, lymphoma, tuberculosis (TB), or infective endocarditis (IE) is suspected.
Interpretation of #7 Foot numbness is peripheral neuropathy. In this case, mononeuritis multiplex or polyneuropathy should be considered. Most likely etiology is vasculitides, especially polyarteritis nodosa. Microscopic polyangiitis is one of candidate. However, kidney function was normal and normal urinalysis except trace of protein was observed.

Vasculitides including polyarteritis nodosa is suspected from #8 Leg Pain.
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are suspected from #9 Unusual scalp feeling and #10 Shoulder Pain.
Lymphoma or another malignant tumor has to be ruled out because she disclosed #11 Fixed 'shotty' nodes in the groins, #12 Mass in oral cavity, and #13 Submucosal mass in upper GI tract.

Multiple myeloma is not candidate in this case. I would introduce one pearl of Dr. Tierney.
The three no’s of myeloma: no FEVER, no splenomegaly, no elevated ALP

Heart failure is apparent because of #14 Dyspnea, #15 Tachypnea, #16 Hypoxia, #17 Tachycardia, Af, #18 Effusions, #19 Wet early crackles, #20 Cardiomegaly, and #21 Pitting edema >40 seconds. Her pulse character was consistent with atrial fibrillation (Af). WET EARLY CRACKLES at the base means early sign of heart failure. Pitting edema >40 seconds was derived from heart failure too. If patient's serum albumin is low, pit recovery time will be within 40 seconds with one exception if there is long standing pitting edema caused by low serum albumin. Long history of edema will cause tissue fibrosis.

Quinke's sign doesn’t mean high specificity of aortic regurgitation (Ar). However, aortic regurgitation due to hypertension is suspected. Of course IE must be ruled out. Interpretation of #24 Ex-smoker, #25 Hyper-expanded chest, and #26 Fibrotic change in the lung are emphysema.

My differential diagnoses are as follows:
Vascular: Less likely Infection: IE, TB (TB is always differentiated in feverish patient in Japan) Neoplastic: Lymphoma, Paraneoplastic syndrome
Autoimmune: Polyarteritis nodosa, Microscopic polyangiitis, PMR/GCA, Still’s disease, SLE, Wegener’s glanulomatosis, Sarcoidosis, Churg-Strauss syndrome
Toxic: Less likely
Metabolic: Diabetes
Trauma/Degenerative: Less likely
Iatrogenic: Less likely Idiopathic: Less likely
Congenital: Less likely
plus she had Af, HTN, Ar, heart failure, and emphysema.

2) What other laboratory study or studies would you consider performing in this patient?

I would order the following tests;
LDH, blood glucose, HbA1C, ferritin, P-ANCA, C-ANCA, and ANA Three sets of blood cultures Cardiac echo to confirm vegetation and kinetics of heart muscle Sputum acid fast stain and cultures for TB Angiogram of celiac, mesenteric, and renal arteries Biopsy of sural nerve and mass in mouth if possible Submucosal mass in upper GI tract should be carefully monitored ALP should be monitored

3) What is your top suspected diagnosis for the MAIN problem in this patient and how would you establish the definitive diagnosis?

In Japan, microscopic polyangiitis is not so rare. Polyarteritis nodosa and Wegener’s glanulomatosis are rare in Japan. But I highly suspect polyarteritis nodosa in this case. I refer one of criteria of Polyarteritis Nodosa. She might have three criteria (bold & italics: 1, 4, and 5). 1990 Criteria For the Classification of Polyarteritis Nodosa

1. Weight loss; 4 kg Loss of 4 kg or more of body weight since illness began, not due to dieting or other factors

2. Livedo reticularis Mottled reticular pattern over the skin or portions of the extremities or torso

3. Testicular pain or tenderness
Pain or tenderness of the testicles, not due to infection, trauma, or other causes

4. Myalgias, weakness or leg tenderness
Diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg muscles

5. Mononeuropathy or polyneuropathy Development of mononeuropathy, multiple mononeuropathys, or polyneuropathy

6. Diastolic BP >90 mm Hg
Development of hypertension with diastolic BP higher than 90 mm Hg

7. Elevated BUN or creatinine
Elevation of BUN >40 mg/dl or creatinine >1.5 mg/dl, not due to dehydration or obstruction

8. Hepatitis B virus Presenece of hepatitis B surface antigen or antibody in serum

9. Arteriographic abnormality
Arteriogram showing aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, fibromuscular dysplasia, or other noninflammatory causes

10. Biopsy of small or medium-sized artery containing PMN
Histologic changes showing the presence of granulocytes or granulocytes and mononuclear leukocytes in the artery wall

For classification purposes, a patient shall be said to have polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificicy of 86.6%. BP = blood pressure; BUN = blood urea nitrogen; PMN = polymorphonuclear neutrophils. Lightfoot RW Jr, Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990;33:1088---93.

PMR/GCA is suspected too. However, these diseases don’t disclose neuropathy. Churg-Strauss syndrome is not likely because she didn’t have history of asthma. SLE and Still’s disease are not highly likely.

Lymphoma is possible. IE and TB have to be ruled out.

Angiogram of celiac, mesenteric, and renal arteries and/or biopsy of sural nerve are needed to establish the diagnosis.
I hope my hypothesis is correct. If it is correct, management of disease will be tough. Her cardiac and lung functions are not good. Opportunistic infection should be CAREFULLY monitored.

Professor Gerald Stein has also provided another excellent assessment below:

1. Problem List
# Fever

# Sweats
# Fatigue

# Weight Loss

# Numbness of her feet
# Dyspnoea
Initial headache
# Leg Pain

# Shoulder Pain
# lymphadenopathy
# tachycardia(?AF)
# Quinke's sign(AR)

# ^JVP
leg edema
# tachypnea

# dullness lung bases

# bibasilar crackles

# decreased light touch feet

# anemia
^ESR large
# 2x3 cm mass arising from the hard palate
chest xp bilat effusions ^ heart shadow
# EGD submucosal mass

1. Assessment
1.Temporal arteritis/GCA evolving from PMR, ? associated with CA S/O CA[gastric lesions CA, MALT]
2. Heart failure, ? IHD, D, AR[?HT related, R/O Lues]
3. DM sensory neuropathy

4. HT

5. Anemia, ? to GCA, R/O GI bleed
6. Gastric Mass, R/O CA, etc
7. Palate mass, R/O CA

2. Anemia studies-Fe, smear, ferritin, etc Biopsies as above+ Temporal Artery Bx, BS, HAIc, ECG, cardiac ECHO, Lues tests,

3. see assessment> Temporal Artery Bx Response to Prednisone 40 mg/d; Aspirin for AF with PPI; Tb eval before Prednisone

Professor Gurpreet Dhaliwal, University of San Francisco has kindly joined this month's opinion on the case. He has also raised some very important and interesting points. Thanks!

I have departed from the suggested format in order to share my general impressions and leading diagnoses:
This 80 year old woman has a subacute inflammatory illness of unknown etiology. Her age increases susceptibility to cancer and infection over other classes of disease (e.g., rheumatologic) and her lifelong smoking substantially increases her probability of cancer

Peripheral neuropathy (with an unusual migratory component) is described. Given her age, I wonder more about paraneoplastic neuropathy than autoimmune conditions, although intermittent arterial ischemia of the limb or the nerves of the limb caused by vasculitis, could mimic these symptoms. The transient leg pain (among other things) makes me wonder about this. Infections are infrequently implicated in peripheral neuropathy.

Generalized lymphadenopathy has a large differential diagnosis including infection (mycobacterial, fungal, viral), malignancy (lymphoma, metastatic carcinoma), and autoimmunity (sarcoid, lupus).

A hard palate mass could be a clue to a disease with a predilection for the hard palate (e.g., Wegeners, Behcets), but as described, it sounds like a torus palatinus

Many features point to new CHF (history of hypertension, new atrial fibrillation, dyspnea, hypoxia, crackles, effusions). I note that the JVP was normal, but this can be a challenging physical exam finding for even experienced practioners. Quinke’s sign is typically associated with chronic AI, but I suspect the specificity is not 100%. The murmur of AI was not detected, it is often quite soft and relies on proper patient positioning.

Her marked normocytic anemia is most likely anemia of chronic inflammatory disease. Bone marrow involvement must be considered with an elevated alkaline phosphatase and normal GGT (suggesting a bone source of alkaline phosphatase), but the other cell lines are not involved. If the alkaline phosphatase elevation was of the liver variety (with no other abnormal liver function tests), then an infiltrative disease of the liver, such as lymphoma or tuberculosis, would merit even stronger consideration.

Finally, there is a mention of a submucosal mass of OGD (EGD), but the location is not noted. Certainly a lymphoma or carcinoma may cause this, perhaps more likely than any infection (e.g., TB) or rheumatologic condition.

The ESR of > 100 must be noted, but it lacks specificity other than confirming the general impression of inflammation -- of unknown etiology in this case.

Here are my hypotheses:

INFECTION: In general, I do not suspect infection here. Other than her age, there is no reason to suspect a chronic indolent infection such as mycobacteria or fungus. Endocarditis would be a very reasonable explanation, although she failed to improve on broad spectrum antibiotics, so SBE seems less unlikely.

AUTOIMMUNITY: The unusual scalp sensation, marked anemia, and ESR > 100 are consistent with giant cell arteritis (temporal arteritis / polymyalgia rheumatica / takayasu’s). GCA is frequent cause of FUO in the elderly and is increasingly recognized as affecting the aorta (e.g., majority of patients with biopsy proven TA have aortic involvement on PET scan.) If so, perhaps this would explain both a sign of aortic insufficiency and limb ischemia. This would be determined by temporal artery biopsy. The lymphadenopathy and oesophageal/gastric mass would be unusual. The features of other vasculitides

MALIGNANCY: The submucosal EGD mass, lymphadenopathy, age, and smoking history make cancers a primary concern. This could represent disseminated lung cancer (hiding in the reported fibrotic area), gastric cancer (based on the EGD mass), or lymphoma. I am most concerned about malignancy, although it is not clear why she has developed atrial fibrillation / heart failure at the same time.

I would pursue the following tests:
Echo to assess for CHF and aortic valve integrity
Biopsy and culture of neck lymph node and EGD mass
If all of the above are unrevealing, I would consider temporal artery biopsy.

The above assessments were very similar to my own and in view of the extensive detail therein, I feel that I cannot surpass them. Hence, I will not go into raptures of my own assessment this month but simply explain what happened next :-)

As Prof Matsumura mentioned above, microscopic polyangiitis (MPA) is not so rare in Japan whereas PAN and Wegener's granulomatosis are rare. However, the MPO-ANCA was found to be slightly positive and hepatitis B & C viruses were negative thereby, in my own opinion, elevating the diagnosis for MPA despite the absence of renal impairment.

However, in MPA renal dysfunction is almost universal when there is the onset of vasculitis. These findings are dichotymous. Hence, the only way to get the diagnosis was to get tissue (that being the issue!) and ruling out infection from Tb and infective endocarditis and excluding malignancy such as a disseminated GI cancer and lymphoma.

In the end, the patient underwent biopsy of the sural nerve which showed a leukocytoclastic vasculitis. There were no granulomata present.

The histopathology final report was consistent with Polyarteritis Nodosum rather than microscopic polyangiitis.

This is in keeping with the opinion of Professor Matsumura but somewhat surprising in view of the elevated MPO-ANCA level.

Tests for endocarditis and tuberculosis were negative.

Repeat gastroscopy revealed ulceration with no malignancy present.

The lesion identified in the hard palate was indeed Torus Palatinus ; a benign lesion of no signficance.

The patient had confirmed heart failure and and aortic regurgitation was confirmed by cardiac echo. This was effectively controlled with standard therapy.

Steroid treatment was commenced (with PPI cover) and there was resolution of most symptoms. Particularly striking was the improvement in malaise, appetite and energy levels (all steroid effects). The patient started walking from being bed bound just a few days earlier and continues to improve on 40mg Prednisolone /day.

For the manifestations, investigations and treatment of PAN, please see UpToDate 16.3

I would like to take this opportunity to thank all of the doctors who took part in January's case responses. The case answer has been posted late for several reasons, but mainly that I have been too busy ! :-o

Stay tuned for more discussions and cases in the future!

Please accept my apologies for the errors in spacing in this article. This seems to be due to a recent error in the Blogger programme.