One of the most difficult cases yet-- the answers!!!

Dear Bloggers

Thank you for waiting for the answers to this very challenging case. The doctors involved here thought of a restricted differential diagnosis from the beginning having considered various underlying causes, they undertook selective testing and had the confirmation of the eventual diagnoses within one week of the patient being admitted to the hospital. 

No CT scan was ever performed to make the diagnosis.

Questions: 

1) From the history and physical examination, please make a problem list.

• Fever
  
  
• Cough
  
  
• Fatigue & Malaise & Appetite Loss
  
  
• Numbness and pain in the right hand
  
  
• Pain in the proximal lower limbs and buttock pain
  
  
• Previous left sided weakness
  
  
• Bilateral chest pain on pressing the chest
  
  
• Left proximal pain on lateral aspect of leg
  
  
• Painful springing of the posterior pelvis
  
  
• Weakness of long and short flexors of the hand, sensory loss affecting the distribution of median and ulnar nerves in right hand. Weakness of adductor muscles of the hand.
  
  
• Arthralgia of MCPs and PIPs of right hand.
  
  
• Antalgic gait with dragging of the left foot
  
  

2) What are the possible differential diagnoses in this case?

This case is somewhat difficult and has a wide set of differential diagnoses. The fact that the patient had a fever for 6 weeks and he did not respond to antibiotic treatment makes a simple infection unlikely. The fact that the patient was reviewed several times at a clinic, and one would hope that basic investigations were performed, makes this a likely Fever of Unknown Origin (FUO)

Infection

Bacterial

• Bacterial endocarditis-  this can cause a generalised vasculitis, fever, malaise, fatigue etc
  
• Osteomyelitis (this would not explain the neurological impairment)
• Tuberculosis (this would not explain the neurological symptoms). If this patient had been living in a high risk area for leprosy (mycobacterium leprae), it might explain the neuropathy but not the cough and chest pain. 
  

Viral

• Parvovirus B19 can cause an upper respiratory infection, constitutional symptoms and joint involvement but cannot explain the neurological impairment. Other viruses that are
   known to cause neuropathies include Varicella zoster (zoster sine herpete) and HIV.
  
  

Neoplastic

• Primary bronchogenic carcinoma with a paraneoplastic neuropathy
  
• Metastatic disease ( affecting chest, bone and causing a paraneoplastic neuropathy
  
• Multiple myeloma (causing bone pain, amyloid induced neuropathy and immune
   suppression with subsequent infection)
  
  

Haematologic

• Lymphoma / Leukaemia with paraneoplastic neuropathy
  

Connective Tissue Disease

• Systemic Lupus Erythematosis
  
• Rheumatoid vasculitis
  
• Wegener’s Granulomatosis (fever, malaise, cough, neuropathy, arthralgia)
  
• Microscopic Polyangiitis (fever, malaise, neuropathy, arthralgia)
  
• Polyarteritis nodosum

Immune

• Guillain-Barre Syndrome – less likely as usually begins in feet and spreads proximally with bilateral weakness.
  

Toxins / Metabolic

• Alcohol (common cause of peripheral neuropathy but usually not so profound) 
  
• Vitamin B6 / B12 deficiency
  
• Lead poisoning

3) What tests would you undertake to investigate this patient's problem including both simple and advanced tests?

Various tests should be performed and include:

• CBC, BUN, Creatinine, Na, K, Liver function, Coagulation, ESR
  
• Urine analysis
  
• Blood, urine and sputum culture
  
• Blood smear
  
• Serum electrophoresis and Bence Jones protein
  
• Autoimmune screen: RhF, ANA, ANCA (MPO and PR3), complement
  
• Thyroid hormones
  
• Xrays of hands, chest lumbar spine and pelvis
  
• Bone marrow examination
  
• Isotopic bone scan
  
• Nerve conduction and electromyographic (EMG) studies 
  

4) Give your top three diagnoses.

• Malignancy e.g. multiple myeloma, metastatic disease
  
• Infection Bacterial endocarditis / osteomyelitis / UTI with disseminated infection
  
• Autoimmune disease e.g. Wegener’s Granulomatosis, Microscopic polyangiitis, polyarteritis nodosum
  

In this case,  the patient underwent several tests. On admission, his haemoglobin was 8.1 with a normal MCV. BUN  and Creatinine were abnormal at 28.5 and 1.4 respectively with normal sodium and potassium levels. Liver function was normal.

Calcium was elevated at 11.6 (corrected).

Urine examination revealed >100 wbc/hpf, 30-49 red cells/hpf, 1+ protein, no evidence of casts and 3+ bacteria.

Initial urine analysis therefore suggested a possible UTI.

From the history, physical examination and basic blood tests, multiple myeloma, bacterial endocarditis, metastatic disease and autoimmune disease were possible diagnoses.

The chest X-ray is below:

 

In view of the chest pain and raised calcium, an isotope bone scan was performed which shows some ‘hot spots’ at the costochondral junctions. The pelvic views show increased uptake at the sacroiliac joints suggesting a possible sacroiliitis.

Abdominal ultrasonography revealed bilateral renal stones only. No other focal abnormality was identified.

Lower limb doppler scans ruled out deep venous thrombosis.

The PTH result was 102 (10-65) suggesting a primary hyperparathyroidism. PTHrP was negative. Vitamin D level was mildly low at 19 with normal above 20.

Neck ultrasonography revealed a  4x4mm mass in the right upper pole of the thyroid.

ESR >100mm/hr

ANA was negative with a positive RhF of 114 (<15).

PR3-ANCA <10

Serum electrophoresis and Bence Jones protein studies refuted the diagnosis of Multiple Myeloma.

MPO-ANCA 546 (<20)

IL2-receptor 1758 (190-650)

Thyroid tests: T3 1.7 (decreased), T4 1.1 (0.8-1.9) TSH 0.8 (within normal limits)

Blood and urine cultures negative

Transthoracic echocardiography revealed no vegetation

MRI scan of the lower vertebral column revealed no metastatic disease or any area consistent with multiple myeloma.

This patient had non-specific symptoms of malaise, fatigue and appetite loss. The fact that both motor and sensory modalities were affected in one hand affecting the distribution of two peripheral nerves i.e. the ulnar and median nerves, makes one consider a distal motor-sensory polyneuropathy; with the addition of arthralgia makes a connective tissue disease much higher as the cause. 

Wegener’s granulomatosis and microscopic polyangiitis would be regarded as the main two diagnoses here, as both can cause neuropathy and are associated with a rise in the serum ANCA. However, 90% of Wegener’s patients have PR3 ANCA versus 10% who have MPO ANCA positivity. The history of a non productive cough makes one consider Wegener’s Granulomatosis which affects both upper and lower respiratory tracts. However, there were none of the very classical upper respiratory features of the disease which can affect the nose, ear etc.

50% of patients with microscopic polyangiitis develop pulmonary disease and this is usually a pulmonary fibrosis.

The arthralgia is a non-specific symptom and can be present in infective, malignant and connective tissue disease but with the above history makes it more likely to be a connective tissue cause.

The majority of patients with microscopic polyangiitis have MPO-ANCA serum positivity and therefore, it was considered to be the most likely underlying diagnosis. Both Wegener’s Granulomatosis and Microscopic polyangiitis can cause renal impairment and hence, a renal biopsy was performed to investigate the underlying cause. The fact that the patient had no casts in the urine but high WBCs and RBCs plus bacteria suggested a UTI rather than a glomerulonephritis-- a lesson learned!

The fact that the patient had lateral leg pain with no joint or nerve stretch signs either suggests a localized myopathy, bone pain or a localized peripheral neuropathy such as a meralgia paraesthetica. However, the bone scan did not reveal bone uptake making a myopathy or neuropathy more likely.

The painful buttocks were likely to be a sacroiliitis as noted by the physical examination and the abnormal uptake in the sacroiliac joints on the bone scan. However, Xray of the sacroiliac joints revealed no obvious abnormality.

The renal biopsy showed: crescentic glomerulonephritis with 50% of the nephrons being involved. Immune staining was consistent with the diagnosis of microscopic polyangiitis.

Likely diagnosis: Microscopic Polyangiitis 

Treatment with pulsed methylprednisolone was started and there was a dramatic drop in fever to the normal range with the patient feeling much better. However, the renal function deteriorated with a creatinine rise to over 3mg/dl in just one week prior to commencing this treatment. Moreover, despite pulse steroids, there was no immediate return of motor function in the affected upper extremity. This was not surprising in view of the prolonged duration it takes peripheral nerves to recover function. Electrophysiological studies were ordered to investigate the likely underlying inflammatory neuropathy.

The patient also underwent neck ultrasonography plus MIBG scanning of the neck.

The underlying diagnoses include:

1) Microscopic polyangiitis  presenting with

• Fever, malaise, fatigue and appetite loss
  
• Motor-sensory polyneuropathy
  
• Arthralgia
  
• Possible meralgia paraesthetica
  
• Anaemia of chronic disease 
• Crescentic glomerulonephritis 
• Positive MPO-ANCA

2) Primary Hyperparathyroidism presenting with 

• Hypercalcaemia
  
• Bilateral rib pain and increased uptake on bone scan
  
• Bilateral renal stones on ultrasound.
  
• Mass in upper pole of right lobe of the thyroid

3) Sick Euthyroid state

Professor Masami Matsumura, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, has again kindly answered the case. 

His answer is frankly amazing and just from the history and examination!

"Thank you very much for showing challenging case! This case is difficult to diagnose, but challenging again.

This patient is previous healthy 61-year-old Japanese man. Patient first symptom was six-week history of cough. The patient thought that this was due to a common cold. Next fever appeared. From these information, I would point out possibilities of autoimmune, infection, and neoplastic diseases. Fatigue and malaise are not high yield symptoms. However, numbness and pain in the right hand, pain in the proximal lower limbs and buttock, and dragging of the left leg appeared. Mono-neuritis multiplex is highly suspected in this case. If physical examination showed findings of mono-neuritis multiplex, vasculitis is most likely.

Questions

1 From the history and physical examination, please make a problem list.

I listed problems as follows;

#1 Cough

#2 Fever

#3 Fatigue and Malaise

#4 Pain in the proximal lower limbs (L5, S1-2)

#5 Buttock pain (L5, S1-2)

#6 Dragging of the left leg

#7 Left sided weakness at age of 30 years

#8 Tachycardia

#9 Obesity, BMI 38.2

#10 Tenderness along the antero-lateral aspect of the ribs bilaterally.

#11 Reduced sensation and pain of the right hand (C6-8)

#12 Joint pain in the MCP joints of the index and middle finger, and several of the PIP joints, suspect polyarthritis

#13 Movements were reduced in extension and flexion of the fingers.

#14 Unable to grip paper between his thumb and index finger (pincer grip) or between the index and middle and the middle and ring finger (C8, T1)

#15 Pain over the sacro-iliac regions (L5, S1-2)

2 What are the possible differential diagnoses in this case?

This patient had cough, fever, and mono-neuritis multiplex.

Differential diagnoses are as follows. Dr. Tierney in SFVA taught this system. These eleven categories are great.

Vascular: Less likely

Infection: Chronic hepatitis, HIV, TB (TB is always differentiated in feverish patient in Japan), Leprosy

Neoplastic: Lymphoma, Paraneoplastic syndrome

Collagen (autoimmune): Microscopic polyangiitis, Polyarteritis nodosa, Goodpasture’s syndrome, Wegener’s granulomatosis, Churg-Straus ssyndrome, SLE, Sarcoidosis, Waldenström’s macroglobulinemia, Cryogloblinemia, Chronic inflammatory demyelinating polyradiculoneuropathy.

Toxic/Metabolic: Diabetes (less likely)

Trauma/Degenerative: Less likely

Iatrogenic: Less likely

Idiopathic: Amyloidosis

Congenital: Less likely

3 What tests would you undertake to investigate this patient's problem including both simple and advanced tests?

I highly suspect vasculitis in this case. In Japan, microscopic polyangiitis is not so rare. Wegener’s glanulomatosis is very rare in Japan. Churg-Strauss syndrome is also rare in any countries. Moreover, this patient doesn’t have history of asthma. Microscopic polyangiitis will involve lung and kidney. Measurement of creatinine, urinalysis, and chest x-ray are essential.

I would order CBC, AST, ALT, LDH, creatinine, Na, K, Cl, ESR, urinalysis, P-ANCA, and chest X-ray.

4 Give your top three differential diagnoses.

1 Microscopic polyangiitis

2 Polyarteritis nodosa

3 Chronic inflammatory demyelinating polyradiculoneuropathy"

Professor Matsumura, as always, thank you very much !

I think the above case and the expert breakdown into the essential elements by Professor Matsumura teaches us important lessons.

For example, autoimmune disease can present with motor-sensory weakness and moreover, a vasculitis can simulate what would initially appear to be a UTI !

As a matter of evidence based treatment, many patients with microscopic polyangiitis require both high dose steroids plus cyclophosphamide in order to settle the inflammation rather than just steroids alone.

This case was certainly a great challenge!