Diagnostic Issues in Systemic Lupus Erythematosis

266 Postgrad Med J 2001;77:266–285 Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from SELF ASSESSMENT QUESTIONS

Diagnostic issues in systemic lupus erythematosis

N Sofat, C Higgens

Answers on p 274. A 24 year old woman was diagnosed with sys- (4) What other tests (apart from 24 hour urine temic lupus erythematosis (SLE) based on a creatinine clearance) are available to measure few months’ history of a photosensitive skin the glomerular ﬁltration rate? rash, predominantly on her face, arthralgia The patient had a 24 hour urinary protein col- involving both hands and wrists, a positive lection, which showed a 24 hour protein measure- antinuclear antibody (ANA) test and a raised ment of 1.8 g. There was no evidence of cellular antinative double stranded DNA antibody casts on urine microscopy. Her blood results were binding level. She was treated with oral as below (normal values are in parentheses): hydroxychloroquine 400 mg daily and short x Sodium 134 mmol/l (135–145) courses of prednisolone during ﬂare-ups. x Potassium 4.5 mmol/l (3.5–5.0) She was reviewed in clinic for her regular x Urea 7.0 mmol/l (2.5–6.7) follow up appointment when she was found to x Creatinine 173 µmol/l (70–115) be hypertensive on repeated measurements of x Haemoglobin 108 g/l (115–160) her blood pressure, an average value being x White cell count 4.5 × 109/l (4.0–11.0) 150/90 mm Hg. She was also urine dipstick x Platelets 130 × 109/l (150–400) positive for blood and protein. IMMUNOLOGY RESULTS Questions x C3 0.30 g/l (0.77–1.63) (1) Which three tests would you ask for next x C4 <0.10 g/l (14–42) from the clinic? x ESR 42 mm/hour (a) 24 hour urine collection for protein x CRP 40 mg/l (0–10) (b) Measurement of erythrocyte sedimenta- x ANA positive at 1:2560 tion rate (ESR) and C reactive protein (CRP) x DNA binding 1000 IU/ml (0–30) Northwick Park and St (5) What is the likely cause of this clinical pic- Marks’ Hospital, (c) Urgent urine microscopy for evidence of Watford Road, casts ture and results?

Harrow, Middlesex (d) Measurement of DNA binding titres (a) Urinary tract infection http://pmj.bmj.com/ HA1 3UJ, UK (e) Renal tract ultrasound scan (b) Dehydration N Sofat (c) Essential hypertension C Higgens (f) Measurement of serum urea, electrolytes, and creatinine (d) SLE associated lupus nephritis Correspondence to: (2) What instructions do you give to a patient (e) Renal amyloidosis Dr Higgens in order to perform a 24 hour urine protein (6) If this patient had persistently lowered com- [email protected] collection? plement levels from the time of her diagnosis, both during remission and relapses of her SLE, Submitted 2 April 2000 (3) Can a 24 hour urine collection under/over on September 24, 2021 by guest. Protected copyright. Accepted 11 July 2000 estimate the glomerular ﬁltration rate? what other diagnosis would you have to consider? (7) Which investigation would you like to do next in order to obtain diagnostic and prognostic information regarding the cause of this women’s renal impairment? (a) Intravenous urogram (b) Renal biopsy (c) Renal tract ultrasound scan (d) Repeat urea and electrolytes (e) Renal EDTA clearance The result of the renal biopsy showed diVuse proliferative glomerulonephritis (World Health Organisation (WHO) grade IV). Figure 1 is an illustration of the changes seen. The patient was initially treated with pulsed methylprednisolone but her renal function did not improve. She consented for treatment with monthly pulsed cyclophosphamide for six months, after which her renal function improved and she remained normotensive. (8) What issues would you have to consider and counsel the patient for when gaining con- Figure 1 Light microscopy of renal biopsy showing proliferative changes throughout the sent from a young woman for treatment with glomerulus consistent with WHO class IV lupus nephritis (haematoxylin and eosin stain). cyclophosphamide?

www.postgradmedj.com Self assessment questions 267

Answers on p 275. Optic disc oedema in ﬁrst degree relatives with Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from diVerent macrovascular risk factors (type 1 Department of Diabetes, Royal diabetes and hypertension) Inﬁrmary, Lauriston Place, Edinburgh EH3 9YW, UK J M Idiculla, R S Lindsay, B W Fleck, J D Walker, B M Frier J M Idiculla R S Lindsay J D Walker BMFrier

Department of Case reports haemorrhages (fig 1B). Visual acuity and Ophthalmology, CASE 1 examination of the left eye were normal. He Princess Alexandra A 43 year old man with type 1 (insulin had no microvascular or macrovascular com- Eye Pavilion, Royal Infirmary, Edinburgh dependent) diabetes for 16 years presented to plications of diabetes and had maintained good B W Fleck the ophthalmology clinic with sudden onset of glycaemic control with glycated haemoglobin painless loss of vision in the right eye. On concentrations consistently below 8% (local Correspondence to: examination, visual acuity in the right eye was non-diabetic range 5.0%–6.5%). He smoked Dr Frier reduced to counting fingers. An aVerent pupil- 20 cigarettes per day, was normotensive, and Submitted 9 June 1999 lary defect was noted and fundoscopy revealed his total plasma cholesterol was normal (4.6 Accepted 13 January 2000 a pale oedematous disc with surface flame mmol/l). Fluorescein angiography was consistent with oedema of the optic disc. Investiga- tions including a computed tomography of the brain, full blood count, erythrocyte sedimentation rate, plasma biochemistry, serum vitamin

B12 concentration, thrombophilia screen, and an autoantibody screen were all normal, and clinical examination by a neurologist detected no additional abnormalities. No improvement in vision occurred during the following 12 months and the right optic disc revealed optic atrophy.

CASE 2 Two months after case 1 had presented with visual loss, his 73 year old mother presented to

the same ophthalmology clinic complaining http://pmj.bmj.com/ that she was experiencing “a curtain of blackness” in her left eye. In the left eye the visual acuity was 1/60 and less than N48 and in the right eye 6/12+2 and N6. Fundal examination revealed swelling of the left optic disc and an aVerent pupillary defect. A lower left altitudinal field defect was demonstrated and investigations similar to those in case 1, did not show on September 24, 2021 by guest. Protected copyright. Figure 1 Case 1: (A) right optic fundus before the development of acute ischaemia; (B) any abnormal findings. The patient had estab- acute ischaemic phase in the right optic fundus; (C) optic fundi six months after the acute episode. The pale disc on the right is suggestive of optic atrophy. lished hypertension treated with amlodipine and doxazosin. She was a non-smoker and her total plasma cholesterol was 6.0 mmol/l. An oral glucose tolerance test was normal. Her vision did not improve over the following eight months, but her left optic fundus showed features of optic atrophy (fig 2).

Questions (1) What are the diagnostic possibilities and what is the most likely diagnosis? (2) What are the risk factors for non-arteritic anterior ischaemic optic neuropathy? Figure 2 Case 2: optic fundi four months after the acute episode. The left disc is paler (3) What are the therapeutic options available consistent with optic atrophy. for this condition?

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An unusual palmoplantar pigmentation Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from

G Sethuraman, M D’Souza, M Vijaikumar, K Karthikeyan, K Ramachandra Rao, D M Thappa

Answers on p 277.

Jawaharlal Institute of Postgraduate Medical Figure 1 Palms showing progressive pigmentation. Figure 3 Discoloration of sclerae. Education and Research, Pondicherry, India: Departments of Dermatology and Sexually Transmitted Diseases G Sethuraman M D’Souza M Vijaikumar K Karthikeyan D M Thappa

Division of Cytogenetics (Department of Figure 2 Fingertips showing progressive pigmentation. Figure 4 Histopathology of the skin lesion. Anatomy) K Ramachandra Rao A 60 year old man had asymptomatic progres- Questions Correspondence to: (1) What is your diagnosis?

sive pigmentation of the palms (fig 1), http://pmj.bmj.com/ Dr Mariette D’Souza, Type V/12, Dhanvantari Nagar, fingertips (fig 2), and soles for the last 20 years. (2) What are the bedside tests by which you JIPMER Campus, Besides this, he had discoloration of his sclerae can confirm your diagnosis? Pondicherry 605 006, India (3) What are the complications of this disease? [email protected] (fig 3). He was well but for low backache and joint pains of a few months’ duration. His- Submitted 14 December 1999 topathological examination of the skin lesion Accepted 13 January 2000 was diagnostic (fig 4). All photographs reproduced with patient’s permission. on September 24, 2021 by guest. Protected copyright.

An unusual cause of tremor in an elderly man

SAWFadilah, A A Raymond, S K Cheong

Answers on p 277. A 70 year old man presented with a two day consisted of vertical head nodding. The upper history of coarse tremors of the head and upper limb tremor was markedly accentuated during limbs. The tremor was evident at rest and it the ﬁnger-nose test and mildly accentuated by became more obvious on movement. There holding the arms outstretched parallel to the were no symptoms of hyperthyroidism or ﬂoor. Neurological examination otherwise history of a similar problem in the past. Apart showed no abnormality. There was mild from slight low back pain, he had been in good prostatic enlargement noted on digital rectal health. His urinary and bowel habits were nor- examination. Chest and abdomen examination mal. He denied taking any drugs. He was a was unremarkable. non-smoker and a teetotaller. The haemoglobin concentration was 86 g/l On examination, the patient appeared pale. with normal red cell indices, white cell count Coarse tremors of the head and upper limbs 2.3 × 109/l, and platelet count 88 × 109/l. were evident at rest. The tremor of the head Microscopic examination of the peripheral

www.postgradmedj.com Self assessment questions 269

blood did not reveal leucoerythroblastosis. The did not reveal any abnormality. An aspirate of Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from erythrocyte sedimentation rate was 102 mm in the bone marrow is shown in fig 2. the first hour. Bone profile was recorded as cal- cium 2.9 mmol/l (normal range 2.2–2.6), phosphorus 1.2 mmol/l (0.8–1.4), and alkaline Questions phosphatase 678 IU/l (40–120). The thyroid, (1) What is the probable diagnosis? renal, and liver profiles were within normal (2) What other investigations should be done limits. The radiograph of the lumbar spine is to confirm the diagnosis? shown in fig 1. Chest radiography and (3) What are the possible causes of the Department of contrasted computed tomogra-phy of the brain tremor in this patient? Haematology and Transplantation, MAKNA-HUKM Cancer Institute, Kuala Lumpur, Malaysia SAWFadilah S K Cheong

Department of Medicine (Division of Neurology), Hospital Universiti Kebangsaan Malaysia (HUKM), Kuala Lumpur, Malaysia A A Raymond

Correspondence to: Dr S Fadilah, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia [email protected]

Submitted 20 September Figure 2 Aspirate of the bone marrow showing a clump of 1999 Figure 1 Radiograph of the lumbar spine showing sclerotic neoplastic cells inﬁltrating the marrow Accepted 20 December 1999 lesions of the lower lumbar vertebrae. (May-Grunwald-Giemsa × 400). http://pmj.bmj.com/ A 35 year man with acromegaly and neck stiVness

A S Kashyap, S Kashyap on September 24, 2021 by guest. Protected copyright. Answers on p 279. A 35 year old man was referred for acromegaly to have surgery and in the interim period was by primary physicians. He complained of mild put on octreotide 100 µg subcutaneously eight diVuse headache and easy fatiguability. Clini- cally he had somatic features of acromegaly and his visual acuity was reduced (6/30: left eye, 6/36 right eye) with a bitemporal superior quadrantanopia. Fundi were normal. He was normotensive and the rest of the clinical examination was normal. His basal hormone concentrations were: growth hormone (ran- Armed Forces Medical dom) >25 mU/l (reference range <10), insulin College, Pune 411 040, India: Department of like growth factor-1 level 210 nmol/l (14–45), Medicine serum alpha subunit not raised (<0.3 IU/l), A S Kashyap prolactin 450 mU/l (60–390), luteinising hormone 8.0 U/l (2.5–9.0), follicle stimulating Department of hormone 7.5 U/l (1.5–9.0), thyroid stimulat- Hospital ing hormone 2.5 mU/l (0.5–4.5), free thyrox- Administration S Kashyap ine 18 pmol/l (10–27), serum cortisol 8 am (basal) 500 nmol/l (160–565), and testoster- Correspondence to: one 20 nmol/l (10–30). Cranial contrast Dr A S Kashyap enhanced computed tomography demon- Submitted 21 May 1999 strated an enhancing sellar mass with suprasel- Figure 1 Computed tomogram showing an enhancing Accepted 13 January 2000 lar extension (ﬁg 1). The patient was advised sellar mass with suprasellar extension.

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hourly, with rapid relief in his headache. Three high density fluid level in the sella and Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from weeks later the patient was brought to the evidence of subarachnoid blood in the basal emergency room with severe diVuse headache, and suprasellar cisterns. nausea, vomiting, diminished vision, and lethargy of five hours’ duration. There was no history of fever. Clinically he was confused and Questions irritable. He had neck stiVness, left sided com- (1) What is the diagnosis? plete third nerve paralysis, and bilateral papil- (2) What are the two most critical alternative loedema. Visual fields and acuity of vision diagnoses? could not be examined. Plain and contrast (3) What is the role of lumbar puncture in enhanced computed tomography showed a this patient?

Joint pains, hoarseness, and deafness

N Younis, I F Casson

Answers on p 280. A 60 year old woman presented with a six week sedimentation rate of 83 mm/hour. She had history of symmetrical joint pains aVecting her normal chest radiography and negative rheu- large joints, associated with night sweats and matoid factor and antinuclear factor anti- weight loss. Recently she had noted hoarseness bodies. of her voice. She had no other relevant history apart from type 2 diabetes for 10 years. Clinical Questions examination revealed stridor and conductive (1) What is the most likely diagnosis and the nerve deafness and the abnormality shown in diVerential diagnosis? ﬁgs 1 and 2. Investigations revealed a (2) What further investigations should be per- normocytic normochromic anaemia with a formed? haemoglobin of 89 g/l and an erythrocyte (3) How would you treat this condition? http://pmj.bmj.com/ on September 24, 2021 by guest. Protected copyright.

Department of Medicine, Royal Liverpool and Broadgreen University Hospital, Liverpool, UK N Younis I F Casson

Correspondence to: Dr N Younis, 7C link, Royal Liverpool and Broadgreen University Hospital, Prescot Street, Liverpool L7 8XP, UK [email protected]

Submitted 1 March 1999 Figure 1 Lateral facial view (photograph reproduced with Figure 2 Frontal facial view (photograph reproduced with Accepted 20 January 2000 patient’s permission). patient’s permission).

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Helicobacter heilmannii Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from

L Williams, M J Dew, L A Murray

Answers on p 281. A 48 year old man was referred to the open chronic gastritis with Helicobacter heilmannii access endoscopy service by his general prac- but no Helicobacter pylori was seen. titioner. He gave a 12 month history of epigas- tric pain and nausea and was receiving Gaviscon. He was an ex-smoker admitting to Questions minimal alcohol intake. (1) What is Helicobacter heilmannii? The gastroscopy was normal but the histol- (2) What does it do? ogy of the biopsy specimens of the gastric (3) What is the clinical significance? antrum (figs 1 and 2) showed superficial (4) Does it require treatment?

Figure 1 Gastric mucosa with H heilmannii on surface (Giemsa stain, oil immersion lens http://pmj.bmj.com/ × 400). on September 24, 2021 by guest. Protected copyright.

Prince Philip Hospital, Bryngwynmawr, Dagen, Llanelli SA14 8QF, Wales, UK L Williams M J Dew L A Murray

Correspondence to: Dr Williams

Submitted 10 January 2000 Accepted 19 April 2000 Figure 2 H heilmannii (Giemsa stain, oil immersion lens × 600).

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Chronic pulmonary suppuration Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from

S Banerjee, P Sundaram, J M Joshi

Answers on p 282. A 25 year old male non-smoker presented to us infective exacerbations requiring antibiotic with a history of cough with mucopurulent treatment. Empirical antituberculosis treat- expectoration and dyspnoea on exertion since ment had been given two years before on the childhood. There were symptoms of frequent basis of symptoms and chest radiographicﬁnd- ings in another institute. On physical examination, there was pallor but clubbing was absent. Chest examination revealed bronchial breath sounds in the right infrascapular area and bilateral coarse crackles. Haematological investigations showed anaemia with a haemoglobin concentration of 120 g/l, but other biochemical parameters were within normal limits. Sputum smear and culture examination were negative for bacteria and acid-fast bacilli. Spirometry showed a restrictive abnormality: forced vital capacity (FVC) 1.5 litres (predicted 4.05 litres), forced expiratory volume in one second

(FEV1) 1.25 litres, and FEV1/FVC ratio of 83%; arterial blood gas analysis gave normal results. His chest radiograph (ﬁg 1) and high resolution computed tomography (HRCT) are as shown in ﬁg 2A and B.

Questions (1) What are the ﬁndings on chest radiograph and HRCT? (2) What is the diVerential diagnosis and how is the diagnosis conﬁrmed? (3) What is the treatment of this condition Figure 1 Chest radiograph showing right lower lobe collapse. and what are the likely complications? http://pmj.bmj.com/ AB on September 24, 2021 by guest. Protected copyright.

Department of Respiratory Medicine, T N Medical College, B Y L Nair Hospital, Mumbai, 400 008 India S Banerjee P Sundaram J M Joshi

Correspondence to: Dr Joshi

Submitted 23 November 1999 Figure 2 (A) HRCT showing right lower lobe collapse with bronchiectasis and (B) HRCT at the level of the trachea Accepted 20 January 2000 showing tracheomegaly.

www.postgradmedj.com Self assessment questions 273

A transient pleural eVusion Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from

M B Frenz

Answers on p 283. A 29 year old Tanzanian man, resident in Great admission he had developed severe headache Britain for five years, presented complaining of and vomiting. On examination he was jaun- persistent cough. He had been an insulin diced, weak, and cachectic. His temperature was dependent diabetic for two years and was well 38.7°C. Examination of the cardiovascular and controlled. A chest radiograph showed a moder- respiratory systems were normal. His liver was ate left pleural eVusion (fig 1). He was followed enlarged 1 cm below the costal margin. There up in clinic without further investigations and a was no meningism, no papilloedema, and there repeat chest radiograph nine months later were no focal neurological signs. showed resolution of the eVusion (fig 2). He returned five months later acutely unwell. He Questions (1) What are the possible causes of a sponta- had lost 5 kg in the previous four weeks and had neously resolving pleural eVusion? developed night sweats. Three days before (2) Name one radiological and one diagnostic procedure that would help in making a diagnosis. (3) What is the most likely cause of his acute illness and how would you treat him?

Milton Keynes General Hospital, Milton Keynes, Buckinghamshire, UK

Correspondence to: http://pmj.bmj.com/ Dr Markus B Frenz, Wycombe Hospital, Queen Alexandra Road, High Wycombe, Bucks HP11 2TT, UK [email protected]

Submitted 21 July 1999 Figure 2 Chest radiograph nine months after initial Accepted 20 January 2000 Figure 1 Chest radiograph taken at initial presentation. presentation. on September 24, 2021 by guest. Protected copyright.

Answers on p 284. A young woman with muscle weakness

N P Singh, S Anuradha, S K Agarwal

Department of Medicine, Maulana A 28 year old woman presented with com- of any orbital puYness, oedema, hoarseness of Azad Medical College and Associated Lok plaints of severe myalgias, muscle cramps and voice, constipation, heat or cold intolerance, Nayak Hospital, New fatigue, of two weeks’ duration. There was a menstrual irregularities, urinary complaints, or Delhi, India history of pain and diYculty in rising from a drug intake. There were no other bone or joint N P Singh squatting position and climbing up stairs. related complaints, fever, alopecia, rash, photo- S Anuradha S K Agarwal These symptoms, initially mild, had become sensitivity, or Raynaud’s phenomena. exacerbated after the patient started cycling, Examination revealed an obese young Correspondence to: which was advised by her physician because of women (weight = 75 kg) with a pulse of 58 Dr N P Singh, DII/356, her weight gain over the preceding one year. beats/min, regular, blood pressure 130/80 mm Pandara Road, New Delhi 110003, India There was no history of any muscle wasting, Hg, and pedal oedema. The chest, cardiovas- [email protected] fasciculations, or any sensory involvement. cular, and abdominal examinations were unre- Submitted 18 November 1999 The patient had gained about 12 kg in markable. Muscle testing revealed a proximal Accepted 13 January 2000 weight over the last year. There was no history muscle weakness (muscle power 3+/5) limited

www.postgradmedj.com 274 Self assessment answers

to the pelvic girdle. There was diVuse tender- Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from ness over all the muscle groups of both the Special laboratory investigations lower limbs. The deep tendon reflexes at the (normal laboratory range in parentheses) ankles were sluggish bilaterally. The rest of the x Thyroid stimulating hormone (TSH): neurological evaluation was normal. 25 mU/l (0.3–7.0) x Total triiodothyronine: 0.55 nmol/l Questions (1.1–3.0) (1) What is the provisional diagnosis and how x Total thyroxine: 13.5 nmol/l will you confirm it? (51.5–167.3) (2) What are the causes of this condition? x Antimicrosomal antibody: 1:1602 (3) What is the most probable aetiology in (positive) this patient and what further investiga- (antithyroid peroxidase (TPO) antibodies: 2 tions would you order to document it? <1:10 ) (4) The special laboratory investigations of x Antithyroglobulin antibody positive x Lupus erythematosus cell, antinuclear the patient are summarised in the box. antibody, rheumatoid factor, Venereal What is the final diagnosis? Disease Research Laboratory negative

SELF ASSESSMENT ANSWERS

Diagnostic issues in systemic lupus specimen, thus avoiding the need for timed erythematosus urine collection.

Q1: Which three tests would you ask for Q3: Can a 24 hour urine collection next from the clinic? under/over estimate the glomerular This patient had blood and protein in her urine filtration rate? on dipstick testing with a high systemic blood It should be noted that a 24 hour urine collec- pressure. These findings should alert the clini- tion for creatinine clearance can overestimate cian to the possibility of renal involvement. the glomerular filtration rate (GFR). This is This is very common in SLE and may be asso- because creatinine is actively secreted by the

ciated with substantial morbidity and mor- renal tubules into the urine as well as being ﬁl- http://pmj.bmj.com/ tality. Careful monitoring of the urine for signs tered by the glomerulus. Low muscle mass by of lupus activity is an important part of the reducing creatinine production will also tend to routine assessment of lupus patients. This overestimate GFR by creatinine clearance. includes answer c, that is analysis of the urine looking particularly for cellular casts. It would Q4: What other tests (apart from 24 hour be important to measure the serum urea, elec- urine creatinine clearance) are available trolytes and creatinine, , as well as to measure the glomerular ﬁltration rate?

answer f on September 24, 2021 by guest. Protected copyright. quantification of the proteinuria with a 24 hour More accurate determinations of GFR include radiolabelled chromium 51EDTA, MAG 3 urine collection, answer a. The latter oVers renograms, and inulin clearance. Inulin clear- important information on the prognosis and ance is an accurate determination of GFR but the response to treatment. is never used in clinical practice nowadays as it is extremely tiresome from a practical view- Q2: What instructions do you give to a point. A MAG 3 renogram can be used, but patient in order to perform a 24 hour chromium 51EDTA is the most commonly used urine protein collection? isotope in clinical practice. The patient is asked to start the 24 hour urine collection on an empty bladder. So, for Q5: What is the likely cause of this instance, if the patient were to first pass urine at clinical picture and results? 9 am in the morning, they would start the urine The answerisd, SLE associated lupus nephritis. collection at this time. This first sample is dis- Most SLE patients who have renal involvement carded. The patient is then asked to empty any have deposits of immune complexes and com- urine passed until 9 am the next morning into plement in the glomerular mesangium. While the bottle provided and then returned to the such lesions may require no specific interven- laboratory for examination. Incomplete 24 tion, they may progress to more serious lesions. hour urine collections due to misunderstand- Glomerulonephritis in SLE is classified ac- ing of instructions or forgetfulness are very cording to histological appearance using the common and will of course underestimate WHO classification, which is as follows (stage urine protein excretion. An alternative is the and histological appearance): estimation of proteinuria by the albumin/ Stage I: normal creatinine ratio in a single early morning urine Stage II: mesangial

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Stage III: focal proliferative mide is definitely superior to azathioprine in Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from glomerulonephritis this setting. A typical regimen uses monthly Stage IV: diVuse proliferative boluses of cyclophosphamide (at a dose of glomerulonephritis approximately 750 mg/m2) for six months or Stage V: membranous glomerulonephritis longer, followed by additional boluses every Stage VI: diVuse sclerosis two or three months for a total of 2–3 years. A Other renal lesions in SLE include tubulo- recent trial has shown that mycophenolate interstitial inflammation and lupus cystitis. mofetil may be equally eVective in the treatment of lupus nephritis.3 Q6: If this patient had persistently Cyclophosphamide is a cytotoxic drug which lowered complement levels from the time interferes with DNA synthesis by alkylating of her diagnosis, both during remission and cross linking DNA strands. Adverse eVects and relapses of her SLE, what other include myelosuppression (white blood cells diagnosis would you have to consider? more than platelets), infections, and haemor- Complement is an organised system of more rhagic cystitis. Mesna is given with pulses in than 20 serum proteins (synthesised predomi- order to prevent the latter complication. nantly in the liver) which helps to protect the Gonadal suppression and temporary or even host from invading organisms. While comple- permanent infertility occur, which is a serious ment is important in host defence, activation of issue in women of childbearing age. The risk of the complement system is detrimental to the ovarian failure also rises with the age of the host in a variety of diseases. In SLE, C3 and C4 woman. Pregnancy tests should be performed levels are often performed clinically. Depressed before treatment is administered and the C3 and C4 levels may indicate disease activity patient should be advised not to conceive dur- and tissue damage, for example glomerulone- ing or for a few months after treatment because phritis. Patients with SLE whose complement of the risks of teratogenicity. Egg collection proteins are within the normal range may fare before treatment can be oVered, but drugs better than those with persistent complement given to stimulate egg production before consumption. However, among SLE patients harvesting can also cause disease flare-ups. there is a higher than normal prevalence of null Other side eVects include nausea, vomiting, alleles for C4; serum C4 may therefore be per- diarrhoea, pulmonary fibrosis, and rashes. sistently depressed when disease is inactive; in For further reading see Hughes1 and Wal- these patients C3 may be a better measure of port.2 disease activity. Inherited deficiencies of the early components of the classical complement We would like to acknowledge Dr David Davies, Consultant pathway (C1, C2, C4) also interfere with the Pathologist at the John RadcliVe Hospital for providing the slide. body’s ability to handle immune complexes, which clinically results in an SLE-like condi- 1 Hughes GRV. Connective tissue diseases. 3rd Ed. Oxford: tion. Blackwell Scientific Publications, 1987. (Contains clinical review of all aspects of SLE.) 2 Walport MJ. Systemic lupus erythematosis. In: Lachmann http://pmj.bmj.com/ Q7: Which investigation would you like to PJ, Peters DK, Rosen FS, et al,eds.Clinical aspects of immunology. 5th Ed. Oxford: Blackwell Scientific Publications, do next in order to obtain diagnostic and 1993: 1161–204. prognostic information regarding the 3 Chan TM, Li FK, Tang CS, et al.EYcacy of mycophenolate in patients with diVuse proliferative lupus nephritis. Hong cause of this women’s renal impairment? Kong-Guangzhou Nephrology Study Group. N Engl J Med A renal biopsy, answer b, would provide 2000;343:1156–62. diagnostic and prognostic information. The various possible histological appearances have been discussed earlier. However, imaging of the Optic disc oedema in first degree on September 24, 2021 by guest. Protected copyright. kidneys before such a procedure is performed relatives with diVerent macrovascular is important to confirm that there are two kid- risk factors (type 1 diabetes and neys present. An ultrasound scan of the renal hypertension) tract is the most commonly used imaging modality; it would also help to exclude coinci- Q1: What are the diagnostic possibilities dental scarring or obstruction, which are man- and what is the most likely diagnosis? datory before renal biopsy. In case 1, the patient who presented with optic disc oedema, possibilities include disorders Q8: What issues would you have to that cause optic disc swelling such as papillitis consider and counsel the patient for when (demyelinative, diabetic), neuroretinitis (for gaining consent from a young woman for example, cat scratch fever), toxoplasma infec- treatment with cyclophosphamide? tion, non-arteritic anterior ischaemic optic Although this patient was initially treated with neuropathy (NAAION), toxic optic neuropa- pulsed corticosteroids, the additional use of thies, and neoplastic compression of the optic cytotoxic agents has become the standard nerve. DIDMOAD (diabetes insipidus, therapy for diVuse proliferative lupus nephritis. diabetes mellitus, optic atrophy, deafness) syn- Azathioprine and cyclophosphamide are the drome is another condition which needs to be most widely used immunosuppressive agents in considered in any diabetic patient with optic this setting and their use is supported by atrophy. The diagnosis of NAAION was made several prospective trials. The most commonly after exclusion of other possible diagnoses. In used regimen is intravenous cyclophosphamide case 2, though the patient did not present to the but it has never been proved in a prospective eye hospital until after the acute episode, the randomised control trial that cyclophospha- clinical picture and negative investigations

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supported the same diagnosis as the first Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from degree relative. Learning points x NAAION is a cause of visual loss Q2: What are the risk factors for associated with oedema of the optic disc. non-arteritic anterior ischaemic optic x Macrovascular risk factors are associated neuropathy? with the development of this condition. Risk factors for NAAION include conditions x A diagnosis of NAAION should be predisposing to macrovascular disease considered when patients present with (diabetes, smoking, hyperlipidaemia, and papilloedema and visual loss. hypertension) and abnormal anatomy of the x Increased awareness of this condition is optic disc (known as “disc at risk”), which is required by doctors screening diabetic described in detail in the discussion below. patients for eye complications of diabetes. Q3: What are the therapeutic options available for this condition? The only eVective therapeutic measure is the optic disc may be inherited. If this is so, prophylactic aspirin therapy to prevent the recognition of a “disc at risk” before the onset involvement of the second eye. However, as of NAAION may allow the introduction of macrovascular risk factors have been found to prophylactic treatment to try to prevent the be associated with this condition, it would be onset of this disease. Though NAAION has reasonable to treat any if they are present. been associated with an increased prevalence and mortality from cardiovascular and cer- Discussion ebrovascular disease,2 the only beneficial NAAION is a frequent cause of visual loss in therapy is treatment with aspirin, reducing the the adult population,1 and is characterised by risk of NAAION in the non-aVected eye.10 an acute loss of central visual acuity and visual There may be a case for screening family field loss (usually inferior altitudinal). It is members of aVected patients and treating them associated with swelling of the optic disc and prophylactically with aspirin. In addition, any flame shaped haemorrhages, either within the identifiable macrovascular risk factors should substance of the optic disc, or in the peripapil- be treated. lary retina. The cause is thought to be acute In diabetic patients, this condition can be ischaemia of the most anterior part of the optic confused with diabetic papillitis, which is a nerve head with occlusion of the posterior cili- relatively benign condition with a good progno- ary circulation. Risk factors for macrovascular sis. It is important to consider this condition disease, including diabetes mellitus, hyper- when patients present with unilateral disc tension, hyperlipidaemia and smoking, are oedema and visual loss, and particularly if they associated with NAAION,2–4 but in addition, have any macrovascular risk factors. Although certain anatomical features of the optic nerve NAAION is familiar to ophthalmologists, an head appear to be underlying predisposing fac- http://pmj.bmj.com/ awareness of this condition needs to be tors. Cross sectional studies have observed that increased among physicians in order to avoid patients with NAAION have a smaller optic unnecessary investigations and diagnostic con- disc and a reduced cup to disc ratio,5 and it has fusion. In particular, it is important that also been suggested that increased branching of doctors or optometrists who screen diabetic central retinal vessels within the disc may also patients for eye complications are aware of its predispose to NAAION.6 The cluster of all or existence. some of these predisposing factors identifies a “disc at risk”. These abnormalities may on September 24, 2021 by guest. Protected copyright. provoke ischaemia secondary to overcrowding Final diagnosis Non-arteritic anterior ischaemic optic neu- of axons as they pass through the lamina crib- ropathy. rosa. Both patients had abnormal optic discs. The discs of case 1 (fig 1A, B, and C; see p 267) 1 Johnson LN, Arnold AC. Incidence of nonarteritic anterior ischemic optic neuropathy: population-based study in the showed additional blood vessels and additional state of Missouri and Los Angeles County, California. J branches of main retinal blood vessels were also Neuro-Ophthalmol 1994;14:38–44. 2 Hayreh SS, Joos KM, Podhajsky PA, et al. Systemic diseases visible. In case 2, the optic discs (fig 2; see p associated with nonarteritic anterior ischemic optic neu- 267) had no physiological cup in either eye. ropathy. Am J Ophthalmol 1994;118:766–80. 3 Chung SM, Gay CA, McRay JA. Nonarteritic ischemic Extra branches and abnormal branching of the optic neuropathy: the impact of tobacco use. Ophthalmology main retinal vessels could also be observed. 1994;101:779–82. 4 GuiVre G. Hematological risk factors for anterior ischemic Each of the patients had diVerent macrovascu- neuropathy. J Neuro-Ophthalmol 1990;10:197–203. lar risk factors and also had features of “disc at 5 Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy IX. Cup-to-disc ratio and its role in pathogen- risk”. The observation of abnormal anatomical esis. Ophthalmology 1987;94:1503–8. features of the optic disc in two generations of 6 Burde RM. Optic disc risk factors for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116:759– the same family suggests that the “disc at risk” 63. may be an inherited characteristic, which is the 7 Berggren L, Thorburn W, Fodstad H. Three cases of nonin- flammatory ischaemic optic neuropathy occurring in the principal predisposing factor to NAAION. same family. Acta Ophthalmol 1974;52:589–95. NAAION has been reported previously to 8 Manor RS. Nonarteritic ischemic optic neuropathy in iden- occur in siblings7–9 and in twins,8 in whom it tical female twins: improvement of visual outcome in one by optic nerve decompression. Arch Ophthalmol 1990;108: was associated with a reduced cup to disc ratio. 1067–8. The present cases further support the possi- 9 Deutsh D, Eting E, Avisar R, et al. Familial anterior ischemic optic neuropathy and papillophlebitis. Am J Ophthalmol bility that these anatomical abnormalities of 1990;110:306–8.

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10 Kupersmith MJ, Frohman L, Sanderson M, et al. Aspirin the dark staining of nappies (diapers). How- Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from reduces the incidence of second eye NAION: a retrospective study. J Neuro-Ophthalmol 1997;17:250–3. ever, the later external manifestations include greyish blue discoloration of the sclera and the cartilage of the external ear. The cutaneous An unusual palmoplantar pigmentation manifestation in the form of fine speckled blue black discoloration occurs mainly in the sun Q1: What is your diagnosis? exposed areas while greenish blue pigmenta- The diagnosis is alkaptonuria. The patient had tion occurs in regions of high sweat gland den- scleral pigmentation with an unusual palmo- sity. The most disturbing and disabling mani- plantar pigmentation and joint involvement. festation of alkaptonuria is the insidious gradually progressive ochronotic arthropathy, Q2: What are the bedside tests by which which generally begins in the third and fourth you can confirm your diagnosis? decade in males and about 10 years later in The following are the simple bedside tests females. Pigmentation of the heart valves, which can be useful in diagnosis: aorta, genitourinary tract, laryngeal, tracheal, Alkali test: addition of few drops of alkali and bronchial cartilages has also been de- such as sodium hydroxide or potassium scribed.34 hydroxide darkens the urine. The diagnosis is usually made from the triad Photographic paper test: application of a drop of degenerative arthritis, ochronotic pigmenta- of alkaptonuric urine over photographic paper tion, and urine that turns black upon alkalini- followed by the addition of few drops of sation.2 Histopathological examination of the sodium hydroxide leads to a black spot on the skin lesion showing homogenised thickened photographic paper. ochronotic pigment in the upper dermal colla- “Black”Benedict’s test:when urine is added to gen further confirms the diagnosis of alkap- Benedict’s reagent, it produces a black col- tonuria.3 oured ring. Treatment is mostly symptomatic; ascorbic Ferric chloride test: addition of ferric chloride acid may be helpful.5 to the patient’s urine produces black colour. The unique feature of this case is the palmoplantar pigmentation, which is exceedingly Q3: What are the complications of this rare. disease? Complications are listed in box 1. Final diagnosis Alkaptonuria. Box 1: Complications of alkaptonuria Musculoskeletal 1 Fernandez-Canon JM, Granadino B, Beltran-Valero de x Arthritis. Bernabe D, et al. The molecular basis of alkaptonuria. Nat Genet 1996;14:19–24. x Kyphosis. 2 Elsas LJ, Longo N, Rosenberg LE. Inherited disorders of aminoacid metabolism and storage. In: Fauci AS, Braun-

x Sciatica. http://pmj.bmj.com/ wald E, Isselbacher KJ, et al,eds.Harrison’s principles of x Disc calciﬁcation and collapse. internal medicine. 14th Ed. New York: McGraw-Hill, 1998: x Ochronotic arthropathy. 2201. 3 Albers SE, Brozena SJ, Glass LF, et al. Alkaptonuria and x Pseudogout. ochronosis: case report and review. J Am Acad Dermatol Cardiovascular 1992;27:609–14. 4 Micali G, Di Stefano AG, Nasca MR, et al. A 46-year-old x Atherosclerosis. man with a 4-year history of diVuse brownish black pigmen- x Valvular stenosis. tation. Endogenous ochronosis (alkaptonuria). Arch Derma- tol 1998;134:100–1. Calculi 5 Pradeep JK, Kehinde FO, Daar AS. Symptomatic response

x Prostatic calculi. to ascorbic acid. BrJUrol1996;77:319–20. on September 24, 2021 by guest. Protected copyright. x Pigmented renal calculi. Others x Deafness. An unusual cause of tremor in an elderly man

Discussion Q1: What is the probable diagnosis? Alkaptonuria is the ﬁrst human disease shown The lumbar spine radiograph shows sclerotic to be inherited as an autosomal recessive trait lesions involving the lower lumbar vertebrae. and is due to the absence of the enzyme homo- The aspirate shows that the bone marrow is gentisic acid oxidase (HGAO) in the liver and densely populated by clumps of neoplastic kidneys.1 AVected homozygotes occur with a cells. The normal haemopoietic cells are almost frequency of around one in 200 000.2 HGAO totally replaced by tumour cells. Neoplastic helps in the degradation of phenylalanine and cells are usually larger than normal haemopoi- tyrosine. Homogentisic acid (HGA) is an etic cells other than the megakaryocytes, and intermediate of this pathway and blockade in they are pleomorphic with regards to size, conversion of HGA to maleyl acetoacetic acid shape, and nuclear characteristic. They are results in accumulation of excessive amounts of commonly cohesive and therefore occur as HGA in the body. This in return is deposited in tight clumps.12It is usually not possible to pre- various connective tissues (ochronosis) and dict the tissue of origin from the cytological subsequently undergoes oxidation and polym- features of the neoplastic cells in smears of erisation.3 bone marrow aspirates. A provisional diagnosis Alkaptonuria is asymptomatic in childhood of metastatic prostatic carcinoma was made and the only sign present in some instances is based on the presence of an enlarged prostate

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on clinical examination, osteosclerotic lesions, Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from and neoplastic cells in the bone marrow. Learning points + Carcinoma of the prostate is a common Q2: What other investigations should be cause of bone marrow infiltration leading done to confirm the diagnosis? to pancytopenia in an elderly man. The metastatic tumour cells in the marrow + The absence of symptoms of prostatism biopsy specimen were positive for prostate spe- does not exclude diseases of the cific antigen using immunohistochemistry prostate. technique that employed monoclonal antibod- + Bone marrow examination is a simple ies. Computed tomography of the abdomen and useful diagnostic tool in the and pelvis showed an irregular thick walled diagnosis of non-haematological malig- prostate and enlarged lymph nodes in the nancies infiltrating the bone marrow. para-aortic and pelvic regions. The patient did + The most important step in the not consent to a transurethral prostatic biopsy. diagnosis of tremor is characterisation of The serum prostate specific antigen (PSA) the tremor in three diVerent positions. level was markedly raised at 120 µg/l. PSA has + Tremor may be the first presentation of generally replaced acid phosphatase for the paraneoplastic syndrome. diagnosis and monitoring of prostatic carcinoma as it has greater sensitivity (especially for early invasive carcinoma) and specificity. the brain computed tomography essentially Marked elevation is indicative of carcinoma, excluded this. The most likely diagnosis is a but concentrations are also increased in paraneoplastic syndrome. The fact that the prostatitis, prostatic ischaemia or infarction, patient’s tremors abated after radiotherapy and benign prostatic hypertrophy, and acute renal hormonal treatment and not after medication failure. Normal concentrations do not exclude (clonazepam and later, primidone) is strong 3 prostatic carcinoma. evidence for this.

Q3: What are the possible causes of the Discussion tremor in this patient? We have demonstrated that this patient had The principal diVerential diagnoses of a tremor disseminated prostatic cancer. The resolution in an elderly man include Parkinson’s disease, of the patient’s tremor after cancer treatment essential tremor, lesions in the midbrain, strongly supports the diagnosis of paraneoplas- cerebellar lesions, endocrine-metabolic dis- tic syndrome. Small cell lung and ovarian can- eases such as thyrotoxicosis and hypoglycae- cers have the highest frequency of paraneoplas- mia, and drugs (such as -agonists, dopamine tic syndromes, although theoretically, any â 4 agonists, alcohol withdrawal, and tricyclic anti- cancer can cause paraneoplastic syndromes. depressants). Like all neurological diseases, the The onset of neurological paraneoplastic syn- single most important step in the diagnostic dromes is usually acute or subacute. Although tremor alone has never been described as being process is the identification of the site of the http://pmj.bmj.com/ lesion. This is almost always possible through a a paraneoplastic syndrome, tremor as part of detailed history and thorough physical exam- subacute cerebellar degeneration and brain 45 ination. The physician must be able to charac- stem encephalitis has. These syndromes, terise the tremor in terms of its site, approxi- however, typically occur with small cell lung mate frequency, amplitude and amplification cancer, and tremor is not a major feature. The or reduction in three diVerent positions (rest, initial symptoms in these syndromes are gait posturing of the arms, and during finger-nose ataxia, dysarthria, diplopia, vertigo, and oscil- 4 testing). Of these features, the latter is the most lopsia. The pathogenesis of these syndromes is on September 24, 2021 by guest. Protected copyright. useful. A tremor, which is present in all three poorly understood, but may be related to positions, points to a lesion in the superior cer- circulating anti-Yo (cerebellar degeneration) ebellar peduncle in the midbrain, near the red and anti-Hu (brain stem encephalitis) autoan- 45 nucleus (thus the term “rubral” tremor). tibodies. The most likely site of the lesion in Rubral tremors are present at rest, and are the present case is the superior cerebellar typically enhanced by posturing of the arms peduncle, presumably due to autoantibodies and more so, by goal directed movements. Par- directed to the midbrain. kinsonian tremors, however, abate with movement. Given the presence of titubation, essen- Final diagnosis tial tremor and a cerebellar lesion are also Disseminated prostatic carcinoma with a para- possible diagnoses.3 There were, however, no neoplastic neurological syndrome. signs of cerebellar dysfunction, and essential 1 Singh G, Krause JR, Breitfeld V. Bone marrow examination tremors do not usually present acutely. The for metastatic tumour. Cancer 1977;40:2317–21. next step in the diagnostic process is to 2 Trizt DB, Doll DC, Ringerberg S, et al. Bone marrow involvement in small cell lung cancer. Cancer 1989;63:763– ascertain the nature of the lesion. Given his age 6. and the acute onset of tremors, a midbrain 3 Lang AE. Movement disorder symptomatology. In: Bradley WG, DaroV RB, Fenichel GM, et al,eds.Neurology in clini- stroke has to be considered first. Computed cal practice: principles of diagnosis and management. Boston: tomography of the brain did not reveal an inf- Butterworth-Heinemann, 1996: 299–320. 4 Posner JB. Paraneoplastic syndromes. In: Bradley WG, arct or haemorrhage in the midbrain, but the DaroV RB, Fenichel GM, et al,eds.Neurology in clinical detection of the former is better on magnetic practice: principles of diagnosis and management. Boston: Butterworth-Heinemann, 1996: 1165–72. resonance imaging. Given the diagnosis of pro- 5 Dalnau JO, Posner JB. Paraneoplastic syndromes aVecting static cancer, a metastatic midbrain tumour is a the nervous system. Semin Oncol 1997;24:318–28. possibility, but the history was too rapid, and

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A 35 year man with acromegaly and neck Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from stiVness Box 2: Pituitary apoplexy—clinical features Q1: What is the diagnosis? x Headache: retro-orbital, frontal, or The diagnosis is pituitary apoplexy. This is diVuse. abrupt destruction of pituitary tissue resulting x Visual impairment: decreased visual from infarction or haemorrhage into the pitui- acuity, visual field defects (most tary, usually into an undiagnosed tumour.1 commonly bitemporal hemianopia, Common predisposing factors are listed in box optic atrophy leading to blindness). 1. x Ophthalmoplegia: III, IV, VI nerve Clinically pituitary apoplexy presentation paresis. may vary from asymptomatic “silent” pituitary x Facial pain and loss of corneal reflex: apoplexy to catastrophic endocrine emergency due to ophthalmic V nerve involvement. with blindness, coma, and haemodynamic x Nausea, vomiting: due to meningism or instability. Clinical features are outlined in box raised intracranial pressure. 2. x Meningism: due to blood or necrotic Numerous endocrinopathies both transient tumour in subarachnoid space. and permanent, may result from pituitary apo- x Altered mentation, ranging from mild lethargy to coma. plexy. Partial or complete hypofunctioning of Hemiparesis and seizures: due to the pituitary appears to be the rule (see box 3). x entrapment of the internal carotid artery in cavernous sinus or vasospasm due to Q2: What are the two most critical subarachnoid haemorrhage (SAH). alternative diagnoses? Anosmia: due to olfactory nerve Two most critical alternative diagnoses in this x compression. patient are aneurysmal SAH and bacterial x Epistaxis and cerebrospinal fluid meningitis. Pituitary apoplexy in its most clas- rhinorrhoea: because of erosion of sic presentation may mimic SAH. Both present haemorrhage through sphenoid sinus with sudden onset of severe headache, im- into the nasal cavity. paired consciousness, and meningeal signs. x Proptosis and eyelid oedema: caused by Similarly both may have sentinel headache, cavernous sinus obliteration. although the interval between the onset of x Hypothalamic compression: disturbed headache and development of mental status sympathetic autoregulation leading to changes tends to be shorter in SAH. Bilateral abnormalities in thermoregulation, third cranial nerve paresis favours pituitary respiration, blood pressure, and cardiac apoplexy; unilateral deficits may be seen in rhythm. both. x Fever. DiVerentiating between pituitary apoplexy and bacterial meningitis may likewise be diYcult because meningeal signs, altered men- http://pmj.bmj.com/ tal status, fever, and headache are features of Box 3: Pituitary apoplexy— both. Ophthalmological findings or hemipare- endocrinopathies3 sis, if present, favour the diagnosis of pituitary x Hypogonadism: 100% apoplexy. x Growth hormone deficiency: 88% x Hyperprolactinaemia: 67% x Acute adrenal insuYciency: 66%

Box 1: Pituitary apoplexy— x Hypothyroidism: 42% on September 24, 2021 by guest. Protected copyright. predisposing causes2 x Diabetes insipidus: 3% x Haemorrhagic infarction of a pituitary tumour. x After obstetric haemorrhage. x Diabetes mellitus and diabetic Mid-brain infarction (basilar artery occlu- ketoacidosis. sion) and cavernous sinus thrombosis, al- x Radiation therapy. though less common, also may need exclusion. x Anticoagulant therapy. x Bleeding disorders. Q3: What is the role of lumbar puncture x Head trauma. in this patient? x Raised intracranial pressure. Lumbar puncture is an unreliable means of x Drugs: bromocriptine, clomiphene, diVerentiating pituitary apoplexy from SAH, thyrotrophin releasing hormone, triple since high red cell count and xanthochromia bolus test, gonadotrophin releasing may sometimes be seen in pituitary apoplexy. hormone, luteinising hormone releasing Pleocytosis and raised cerebrospinal ﬂuid pro- hormone analogue (goserelin), teins are common to both bacterial meningitis isosorbide, chlorpromazine, oestrogens. and pituitary apoplexy, and do not provide x Carotid angiography and much assistance in distinguishing between pneumoencephalography. them. Moreover in suspected pituitary apo- Mechanical ventilation. x plexy lumbar puncture may be dangerous, Cardiac surgery, lumbar laminectomy, x because it may precipitate uncal herniation. haemodialysis. Computed tomography and magnetic resonance imaging are most likely to be helpful by

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diVerential diagnoses are listed in box 1. The Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from Box 4: Neuroimaging in pituitary causes of saddle nose deformity are listed in 5 apoplexy box 2. Computed tomography x Computed tomography of the head is most useful in the acute setting (24–48 Box 1: DiVerential diagnoses hours). x Wegener’s granulomatosis. x 1.5 mm thin sections in coronal plane x Polyarteritis nodosa. through pituitary fossa with intravenous x Takayasu’s arteritis. contrast are highly sensitive. x Giant cell arteritis. x High density or inhomogeneous x Rheumatoid arthritis. gland, with or without evidence of x Rheumatic fever. subarachnoid blood ring enhancement x Sarcoidosis. or a high density fluid level, may be seen. x Malignancy. Magnetic resonance imaging x Systemic lupus erythematosus. x Acute haemorrhage (<7 days): hypointense or isointense to brain on T1 and T2 weighted images. x Subacute stage (7–14 days) increased Box 2: Causes of saddle nose deformity intensity in periphery of the haematoma x Relapsing polychondritis. (owing to haemoglobin breakdown x Wegener’s granulomatosis. products such as methaemoglobin), with x Trauma. centre remaining hypointense. x Congenital syphilis. x Chronic stage (>14 days) entire x Intranasal cocaine use. haematoma appears bright on T1 and x Rheumatoid arthritis. T2 images. x Racial/inherited. x Ectodermal dysplasia. x Down’s syndrome. x Leprosy. demonstrating a sellar mass even if evidence of acute haemorrhage is not obvious (see box 4).4 Q2: What further investigations should be Follow up The patient was managed with intravenous performed? Further investigations should include laryngo- hydrocortisone and other supportive measures. scopy and bronchoscopy to define the extent Emergency transsphenoidal removal of a of laryngotracheal involvement. Computed necrotic and haemorrhagic pituitary macroad- tomography of the upper airway is a useful enoma was done. Immunohistochemistry re- investigation1 and to a lesser extent pulmonary vealed growth hormone secreting adenoma. He function tests. Serum antineutrophil cytoplas- http://pmj.bmj.com/ made a rapid symptomatic recovery and mic antibody should be checked to exclude the features of meningism subsided over the next possibility of Wegener’s granulomatosis. Tissue two days. Further endocrinological evaluation diagnosis can be confirmed by a biopsy is planned to determine the nature and degree specimen in patients with auricular chondritis of hormone deficits. but is not essential.2 Final diagnosis Q3: How would you treat this condition?

Pituitary apoplexy. on September 24, 2021 by guest. Protected copyright. Mild episodes of auricular and nasal chondritis and seronegative arthritis usually respond to 1 Vance ML. Hypopituitarism. N Engl J Med 1994;330:1651– non-steroidal inﬂammatory drugs with or 62. 2 Reid RL, Quigley ME, Yen SSC. Pituitary apoplexy. Arch without a low dosage of corticosteroid. More Neurol 1985;42:712–19. serious manifestations such as airway involve- 3 Veldhius JD, Hammond JM. Endocrine function after spontaneous infarction of the human pituitary: report, review ment, as in this patient, require high dose and reappraisal. Endocr Rev 1980;1:100–7. prednisolone and often cytotoxic drugs are 4 Rolih CA, Ober KP. Pituitary apoplexy. Endocrinol Metab Clin North Am 1993;22:291–302. needed. 5 Ostrov SG, Quencer RM, HoVman JC, et al. Hemorrhage within pituitary adenomas: how often associated with pituitary apoplexy syndrome? Am J Roentgenol 1989;153:153–60. Discussion Relapsing polychondritis is an episodic systemic disorder characterised by recurrent widespread destruction involving cartilaginous structures. Attacks tend to vary in severity and Joint pains, hoarseness, and deafness duration usually lasting for days to weeks before resolving spontaneously. Presenting Q1: What is the most likely diagnosis and symptoms are most frequently auricular chon- the diVerential diagnosis? dritis (90%), polyarthritis (80%), nasal chon- The most likely diagnosis is relapsing poly- dritis (60%), ocular involvement (50%), and chondritis. The combination of joint pains, respiratory tract involvement (55%).2 Respira- saddle nose deformity and hoarseness of the tory involvement is the most serious manifesta- voice, suggesting laryngeal or tracheal involve- tion of relapsing polychondritis. Oedema, ment, makes the diagnosis of relapsing poly- stenosis, and collapse and disintegration of the chondritis the most likely. The other possible cartilage results in tracheobronchial chondritis

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and subglottic stenosis causing collapse of the Helicobacter heilmannii Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from trachea and bronchi, pulmonary infections, and even asphyxia.3 Computed tomography is Q1: What is Helicobacter heilmannii? useful in assessing the respiratory involvement Helicobacter heilmannii was first described in of the disease.1 Nasal chondritis develops often 1987 as a Gram negative urease producing and repeated attacks may cause cartilage tightly coiled bacillus, morphologically distinct collapse with characteristic saddle nose de- to Helicobacter pylori and labelled Gastrospiril- formity. Such changes may appear in the lum hominis.1 It has been reclassified as a non- absence of clinically evident inflammation.4 pylori Helicobacter spp and found to have a 90% Cardiovascular manifestations include sys- homology in the 16s RNA nucleotide sequence temic and central nervous system arteritis, aor- to H pylori.2 Following the description of a large tic aneurysm, and valvular insuYciency. The series of patients by a German pathologist in auricle is classically painful and the commonest 1991 the organism has been renamed H site of involvement.4 In addition the middle ear heilmannii.3 It is now recognised as the may be involved with eustachian tube dysfunc- commonest non-pylori species in humans with tion and collapse resulting in otitis media. The an average incidence in a civilised human auditory-vestibular apparatus may be involved, population of 0.3%.3 Culture of this bacillus is resulting in sensorineural deafness. This is diYcult and its method of detection varies thought to be due to arteritis involving the world wide and as such its prevalence varies internal auditory artery and is the likely cause geographically.4 H heilmannii shows little varia- of deafness in this patient.5 Approximately 25% tion but reported numbers in clinical series are of cases have coexistent diseases especially small.2 It bears a close genotypic profile to autoimmune diseases, systemic sclerosis, sys- Helicobacter felis, which is usually found in the temic lupus erythematosus, rheumatoid arthri- gastric mucosa of cats and dogs, and this has tis, Sjögren’s syndrome, thyroid disease, ulcera- prompted theories of zoonotic transmission. tive colitis, and Wegener’s granulomatosis.4 No Seventy per cent of patients with H heilmannii specific laboratory test exists for relapsing infection have contact with pets.5 polychondritis and findings are often non- specific: raised erythrocyte sedimentation rate, Q2: What does it do? leukocytosis, anaemia, raised antistreptolysin-O H heilmannii has been shown to cause a titres, and occasionally positive rheumatoid neutrophilic inflammatory response in the gas- factor or antinuclear factor.4 Detection of tric mucosa and in some reports mucosal atro- autoantibodies to type II collagen present in phy, metaplasia, and dysplasia. The degree of cartilage and sclera, and cell mediated immu- inflammation seen is to a lesser extent than that nity to cartilage components in patients with seen with H pylori. There have been sugges- relapsing polychondritis, suggest an autoim- tions of a synergistic relationship with H pylori, mune aetiology.6 Histology of aVected tissues although other studies show a protective eVect shows perichondrial inflammation, with loss of of against .67 H heilmannii H pylori http://pmj.bmj.com/ basophilic staining of a cartilage matrix and areas of cartilage destruction with replacement Q3: What is the clinical significance? of fibrous tissues.7 The natural history is Heilman in 1991 showed an association unpredictable and may have an episodic, between infection and gastrointestinal disease smouldering, or a fulminant course.4 Mortality in humans.2 Further reports support an associ- is usually secondary from respiratory complica- ation with predominantly superficial gastritis.27 tions such as airway collapse or pneumonia, There are a few case reports of an association 28 aneurysm rupture, valvular heart disease, or with peptic ulcer disease and gastric cancer. on September 24, 2021 by guest. Protected copyright. vasculitis. Infective complications or malignancy from immunosuppressive drugs may Q4: Does it require treatment? occur. Most severe cases require steroids or H heilmannii has been shown to spontaneously immunosuppressant drugs. disappear together with total resolution of inflammatory change.27 However, chronicity Final diagnosis has been described and there is evidence to Relapsing polychondritis. suggest susceptibility to H pylori eradication therapy.28 Whether it is a true pathogen remains an open question. 1 Port JL, Khan A, Barbu RR. Computed tomography of In this case, as the man was symptomatic, it relapsing polychondritis. Comput Med Imaging Graph 1993;17:119–23. was decided to treat him with H pylori eradica- 2 Damiani JM, Leveine HL. Relapsing polychondritis—report tion therapy and to continue on a proton pump of ten cases. Laryngoscope 1979;89:929–46. 3 Eng J, Sabanathan S. Airway complications in relapsing inhibitor. He became asymptomatic after the polychondritis. Ann Thorac Surg 1991;51:686–92. initial eradication treatment and is now in the 4 Herman J. Polychondritis. In: Kelley WN, Harris ED Jr, Ruddy S, et al,eds.Textbook of rheumatology. 4th Ed. process of stopping all treatment. Philadelphia: WB Saunders, 1993: 1400–11. 5 Cody DTR, Sones DA. Relapsing polychondritis: audioves- tibular manifestations. Laryngoscope 1971;81:1208. 1 Dent JC, McNulty CAM, U JC, . Spiral organisms in 6 Fiodart JM, Abe S, Martin GR, et al. Antibodies to type II V et al the gastric antrum. 1987; :96. collagen in relapsing polychondritis. N Engl J Med Lancet ii 1978;229:1203–7. 2 Kusters JG, Kuipers EJ. Non-pylori helicobacter infections 7 Verity MA, Larson WM, Madden SC. Relapsing in humans. Eur J Gastroenterol Hepatol 1998;10:239–40. polychondritis: report of two necropsied cases with histo- 3 Heilman KL, Borchard F. Gastritis due to spiral shaped chemical investigations of the cartilage lesions. Am J Pathol bacteria other than Helicobacter pylori: clinical, histological 1963;42:251. and ultrastructural findings. Gut 1991;32:137–40. 4 Hazell SL. Isolation of Helicobacter heilmannii from human tissues. Eur J Clin Microbiol Infect Dis 1996;15:4–9.

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5 Stolte M, Wellens E, Bethke B, et al. Helicobacter heilman- Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from nii (formerly Gastrospirillum hominis) gastritis; an infection Box 1: Causes of bronchiectasis transmitted by animals? Scand J Gastroenterol 1994;29: 1061–4. Congenital causes 6 Yali Z, Yamada N, Wen M, et al. Gastrospirillum hominis and Helicobacter pylori infection in Thai individuals. Com- x Structural defects—for example, parison of histopathological changes of gastric mucosa. tracheobronchomegaly, bronchomalacia, Pathol Int 1998;48:507–11. 7 Debongnie JC, Donnay M, Mairesse J. Gastrospirillum pulmonary sequestration. hominis (Helicobacter heilmannii): a cause of gastritis sometimes transient, better diagnosed by touch cytology? x Ciliary defects—for example, Am J Gastroenterol 1995;90:411–15. Kartagener’s syndrome, Young’s 8 Goddard AF, Logan RPH, Atherton JC, et al. Healing of a duodenal ulcer after eradication of Helicobacter heilmannii. syndrome. Lancet 1997;349:1815–16. x Immunodeficiency syndromes. x Metabolic defects—for example, cystic Chronic pulmonary suppuration fibrosis, á1-antitrypsin deficiency. Acquired causes Q1: What are the findings on chest x Infections in childhood. radiograph and HRCT? (see p 272) The chest radiograph and HRCT show x Secondary due to bronchial obstruction collapse of the right lower lobe with areas of due to a tumour or foreign body or hilar cavitation and bronchiectasis. Areas of fibrosis glands causing bronchial obstruction. due to old infection are seen in anterior and x Associated disorders of immunity—for posterior segments of the left upper lobe. There example, autoimmune diseases. is an increase in the tracheal diameter sugges- x Bronchopulmonary aspergillosis. tive of tracheomegaly.

Q2: What is the diVerential diagnosis and how is the diagnosis confirmed? postural drainage and antibiotics. Occasionally The diVerential diagnoses to be considered in a tracheobronchomegaly may progress to exten- patient with chronic pulmonary suppurative sive tracheomalacia due to softening of sup- symptoms include bronchiectasis, lung ab- porting cartilages, as in our case. In some scess, and cystic fibrosis, The causes of severe cases the trachea becomes distorted and 1 permanently narrowed resulting in diVuse tra- bronchiectasis can be congenital or acquired 2 as shown in box 1. cheal stenosis and respiratory failure occurs. On computed tomography the coronal Nasal continuous positive airway pressure pro- diameter of the trachea measured 28 mm in vides optimal splinting of the airways to our case and confirmed the diagnosis of prevent dynamic collapse caused by trache- tracheobronchomegaly. Three dimensional vir- omalacia. Expanding wire shunts or Y stents have been used in adults with tracheomalacia tual reconstruction technique (3DVRT) (fig 3) 2 further showed dilatation of the trachea and the with good results. right main bronchus. Bronchoscopy showed http://pmj.bmj.com/ presence of excessive collapsibility of the Discussion trachea suggestive of tracheomalacia. Tracheobronchomegaly is a distinctive, clinico- radiological condition consisting of marked Q3: What is the treatment of this dilatation of the trachea and major bronchi condition and what are the likely associated with chronic respiratory tract infec- complications? tion and bronchiectasis. The syndrome is rare Treatment of tracheobronchomegaly is aimed and often begins in childhood, although it is fre- at minimising damage resulting from stasis of quently diagnosed in the fourth or fifth decade, on September 24, 2021 by guest. Protected copyright. secretions and infections and consists of and is thought to be due to a congenital defect of the elastic and muscle fibres of the tracheobronchial tree.34 A familial form with a possible autosomal recessive inheritance has been reported.5 Acquired forms of tracheobronchomegaly may occur as a complication of diVuse pulmonary fibrosis, due to mechanical ventilation in preterm infants or in congenital immu- noglobulin deficiency.36However, the degree of tracheal dilatation seen with diVuse pulmonary fibrosis is usually mild,6 and diverticula forma- tion seen in the congenital form is not seen in the acquired form of tracheobronchomegaly. Clinical symptoms range from asymptomatic to symptoms indistinguishable from those caused by chronic bronchitis or bronchiectasis. Stridor or respiratory failure may suggest associated tracheomalacia or tracheal stenosis. The diagnosis of tracheobronchomegaly may be missed unless specifically looked for. Hence the routine measurement of tracheal diameter on Figure 3 3DVRT showing dilatation of the trachea and chest radiographs and computed tomograms in right main bronchus. cases of chronic pulmonary suppuration is

www.postgradmedj.com Self assessment answers 283 Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from Learning points Box 1: Common causes of spontaneous x Tracheobronchomegaly is a rare cause of resolving pleural eVusion chronic pulmonary suppuration. Infections x Tuberculosis. x Tracheobronchomegaly can be of Parapneumonic eVusion (non-empyemic). congenital or acquired aetiology. x Connective tissue disease x Computed tomography measurement of x Systemic lupus erythematosus. coronal diameter of trachea greater than x Rheumatoid arthritis. 18.2 + 3SD (1SD=1.2 mm), in males, Cardiovascular 15.2 + 3SD (1SD= 1.4 mm) in females x Heart failure. is diagnostic of tracheobronchomegaly. x Pulmonary infarction. x Tracheomalacia with respiratory failure Drug induced (rare) is a life threatening complication. x Bromocriptine. x Treatment consists of postural drainage, x Dantrolene sodium. antibiotics, and nasal continuous positive Trauma airway pressure or tracheal splints for associated tracheomalacia. In view of the headache with vomiting as one of the main complaints a lumbar puncture worthwhile. Tracheobronchomegaly is defined should be done after exclusion of raised intrac- by an increase in transverse diameter of the ranial pressure. Computed tomography of the trachea and mainstem bronchi of 3SDs or brain was normal and cerebrospinal fluid greater. The mean (SD) tracheal diameter on analysis from a lumbar puncture showed the computed tomography is 18.2 (1.2) mm in following: males and 15.2 (1.4) mm in females.7 The x 55 white cells/ml with 70% monocytes. diagnosis of tracheobronchomegaly can also be x Glucose 1.6 mmol/l (with a blood glucose confirmed by bronchography, computed tom- 5.7 mmol/l). ography, virtual bronchoscopy, and magnetic x Gram stain and Ziehl-Neelsen stain for resonance imaging. Demonstration of exces- acid-fast and alcohol-fast bacilli were nega- sive collapsibility of the trachea on expiration tive. by flow volume loop, fluoroscopy, and bronchoscopy confirms associated tracheomalacia. Q3: What is the most likely cause of his acute illness and how would you treat Final diagnosis him? Tracheobronchomegaly (Mounier-Kuhn syn- The two above mentioned investigations and drome) with tracheomalacia. the clinical course during his acute illness support the diagnosis of miliary tuberculosis with

meningeal involvement. He was treated with http://pmj.bmj.com/ 1 Seaton A, Seaton D, Leitch AG. Bronchiectasis. Crofton and Douglas’s respiratory diseases. 4th Ed. New Delhi: Oxford University Press, 1989: 601–29. 2 Cullard PH, Freitag L, Reynart MS, et al. Respiratory failure due to tracheobronchomalacia. Thorax 1996;51: 224–6 . 3 Schoor VJ, Joos G, Pauwels R. Tracheobronchomegaly—the Mounier Kuhn syndrome: report of two cases and a review of literature. Eur Respir J 1991;4:1303–6. 4 Katz I, LeVine M, Herman P. Tracheobronchomegaly (the

Mounier Kuhn syndrome). Am J Roentgenol 1962;88:1084– on September 24, 2021 by guest. Protected copyright. 94. 5 Johnston RF, Green RA. Tracheobronchomegaly. Report of ﬁve cases and demonstration of familial occurrence. Am Rev Respir Dis 1965;91:35–50. 6 Schraufnagel DE, Boomsma JD. Tracheobronchomegaly. Chest 1992;102:1307. 7 Dunne MG, Reiner B. CT features of tracheobronchomegaly. J Comput Assist Tomogr 1988;12:388–91.

A transient pleural eVusion

Q1: What are the possible causes of a spontaneously resolving pleural eVusion? The most common causes of spontaneous resolving pleural eVusion are given in box 1.1

Q2: Name one radiological and one diagnostic procedure that would help in making a diagnosis As part of routine investigation a chest radiograph would be the simplest radiological investigation to exclude pulmonary pathology as a cause of his acute presentation. His chest Figure 1 Close-up of chest radiograph taken during the radiograph showed miliary shadowing but no acute presentation showing the area above the left other abnormality (ﬁg 1). diaphragm.

www.postgradmedj.com 284 Self assessment answers

isoniazid, rifampicin, ethambutol, and pyrazi- Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from namide and improved slowly over the next Box 1: Laboratory investigations month. His cerebrospinal fluid grew Mycobac- (normal laboratory range in terium tuberculosis five weeks after the lumbar parentheses) puncture, fully sensitive to all four antitubercu- x Serum cholesterol: 6.0 mmol/l (<5.2) losis drugs prescribed. A repeat chest radio- x Serum creatinine: 88.4 µmol/l graph after four months was normal and he (53.0–88.4) returned to work as a meat factory worker. x Aspartate aminotransferase: 88 IU/l (<30) Discussion x Alanine aminotransferase: 70 IU/l (<30) Although no further investigations were under- x LDH: 2500 IU/l (0–150) taken during the initial presentation with a x Creatine kinase (total): 1795 IU/l pleural eVusion, tuberculosis was the most (0–100) likely cause. Pleural eVusion can be a manifes- x EMG: reduced amplitude of muscle unit tation of primary and post-primary tuberculo- potentials sis. Primary tuberculous eVusion occurs most x Muscle biopsy: normal frequently in young adults.2 The eVusion is usually unilateral and of moderate size. The diagnosis is best made by pleural biopsy specimens, which show pleural granulomata and involvement suggests a primary muscle in- positive cultures in 60%–80% of patients with volvement, that is, a myopathy. proved tuberculosis and can be improved by To confirm the diagnosis of a myopathy, bio- using multiple pleural biopsy specimens.3 chemical tests such as estimation of serum Enhanced culture yield can be achieved by transaminases, lactic acid dehydrogenase using bedside inoculation of pleural fluid.4 (LDH), aldolase, and creatine kinase are very Routine analysis of pleural fluid for glucose, useful. Of these, the analysis of creatine kinase protein, and acid-fast organisms are of little levels is the most sensitive indicator and meas- help in making a diagnosis. The value of ure of muscle damage. Electrodiagnostic tests adenosine deaminase levels in pleural aspirate especially an electromyogram (EMG) are of is controversial. The prognosis of patients with great value in the diagnosis of muscle disor- tuberculous pleural eVusion depends on the ders. A muscle biopsy can be of great diagnos- treatment chosen. Simple bed rest commonly tic value in certain muscle storage disorders, results in complete absorption of the eVusion denervative disorders, mitochondrial myopa- but the incidence of subsequent pulmonary or thies, polymyositis, and in some muscle dystro- extrapulmonary tuberculosis is high. This is a phies. particular problem in patients with immuno- The laboratory investigations of this patient suppression. Treatment with standard antitu- summarised in box 1 reveal a markedly raised berculosis drugs is indicated in all cases and creatine kinase and LDH levels and an EMG

reduces the subsequent development of pul- pattern all confirming the diagnosis of a http://pmj.bmj.com/ monary or extrapulmonary tuberculosis.5 In myopathy. view of the increasing incidence of tuberculosis in Great Britain all attempts should be made to Q2: What are the causes of this condition? diagnose and treat patients with tuberculous Muscle disorders are classified syndromically pleural eVusion. into acute or subacute, chronic, and episodic depending upon the onset and progress (see Final diagnosis box 2). Spontaneously resolving tuberculous pleural Pain and tenderness associated with muscle on September 24, 2021 by guest. Protected copyright. eVusion with subsequent miliary tuberculosis. disorders are characteristic of a few specific disorders listed in box 3. IthankDrJIGStrang for constructive comments.

1 Fraser RG, Paré JAP, Paré PD, et al. Pleural eVusion. Diag- Box 2: classification of muscle diseases nosis of diseases of the chest. 3rd Ed. Philadelphia: WB Saun- ders, 1991: 2713–39. Acute/subacute onset 2 Valdes L, Alvarez D, Valle JM, et al. The etiology of pleural Idiopathic polymyositis/dermatomyositis. eVusions in an area with high incidence of tuberculosis. x Chest 1996;109:158–62. x Viral polymyositis. 3 Mungall IP, Cowen PN, Cooke NT, et al. Multiple pleural x Botulism. biopsy with the Abrams needle. Thorax 1980;35:600–2. 4 Maartens G, Bateman ED. Tuberculous pleural eVusions: x Organophosphorus poisoning. increased culture yield with bedside inoculation of pleural fluid and poor diagnostic value of adenosine deaminase. Chronic onset Thorax 1991;46:96–9. x Muscle dystrophies. 5 Pines A. The results of chemotherapy in the treatment of x Chronic polymyositis. tuberculous pleural eVusions. BMJ 1957;ii:863–8. x Endocrine myopathies. x Mitochondrial and other congenital myopathies. A young woman with muscle weakness x Storage disorders. Episodic Q1: What is the provisional diagnosis and x Periodic paralysis. how will you confirm it? x Myasthenia gravis. The characteristic features of muscle pain, a x Exercise intolerance. predominant proximal muscle weakness, sluggish ankle jerks, and absence of sensory

www.postgradmedj.com Self assessment answers 285 Postgrad Med J: first published as 10.1136/pmj.77.906.268 on 1 April 2001. Downloaded from Box 3: Muscle disorders with Box 4: Learning points pain/tenderness x Though unusual, myopathy may be the x Connective tissue disorders: lupus presenting feature of hypothyroidism. erythematosus, polymyositis, x All patients with a myopathy of obscure polyarteritis nodosa, Sjögren’s origin should be investigated to exclude syndrome, mixed connective tissue disorders like hypothyroidism. disease. x Localised multifocal fibrositis. x Trichinosis. and symptoms of hypothyroidism, as seen in x Myopathy of myoglobinuria and this patient, is however unusual. Most such McArdle’s syndrome. cases have been found to be of autoimmune x Viral polymyositis. origin.4 x Hypothyroidism. Impaired energy metabolism that limits force generation, a reduction in the myosin ATPase activity reflected by the slow contraction and Q3: What is the most probable aetiology relaxation of the reflexes, and an impaired cal- in this patient and what further cium uptake by the sarcoplasmic reticulum are investigations would you order to the proposed pathogenetic mechanisms of document it? muscle weakness in hypothyroidism.5 In this young woman with myopathy, a history The spectrum of structural changes in the of weight gain, and bradycardia on examina- skeletal muscles in hypothyroid myopathy is a tion, an endocrine myopathy, especially hypo- continuum. The changes in muscle biopsy cor- thyroidism, must be excluded. Also, connective relate with the severity of hypothyroidism and tissue disorders such as polymyositis and lupus consist of increasing type 2 fibre atrophy and erythematosus should be ruled out with appro- central nuclear counts on light microscopy, and priate investigations. excessive glycogen accumulation and increased numbers of mitochondria on electron micros- Q4: The special laboratory investigations copy. The changes on muscle biopsy also of the patient are summarised on p 274. depend on the amount of tissue available for What is the final diagnosis? assessment.6 Raised TSH along with a low triiodothyronine Substitutive therapy with thyroxine is used in confirm the diagnosis of hypothyroidism. The the treatment of hypothyroid myopathy. presence of anti-TPO antibodies provides con- Marked improvement in symptoms and labora- clusive evidence of an autoimmune thyroid tory parameters occurs on attainment of an disease with resultant hypothyroidism. euthyroid state. The present patient was The patient was given thyroxine replenish- unusual in that she presented with only ment and there was marked symptomatic features of a primary muscle disorder without

improvement and the creatine kinase, LDH, pointers to an underlying hypothyroid state. http://pmj.bmj.com/ and TSH levels returned to normal. The learning points from this case are summarised in box 4. Discussion Hypothyroidism is associated with a wide range Final diagnosis of muscle disturbances varying from myalgias, Autoimmune thyroid disease, hypothyroidism, to a true myopathy to rhabdomyolysis.12 Two and hypothyroid myopathy. classic syndromes of hypothyroid muscle disorders have been described: the Kocher-Debré- 1 Lochmuller H, Reimers CD, Fischer P, et al. Exercise- on September 24, 2021 by guest. Protected copyright. induced myalgia in hypothyroidism. Clin Invest Sémélaigne syndrome (cretinism associated 1993;71:999–1001. with myopathy) and HoVmann’s syndrome 2 Sekine N, Yamamoto M, Michikawa K, et al. Rhabdomyoly- (myxoedema in childhood or adult life associ- sis and acute renal failure in a patient with hypothyroidism. Intern Med 1993;32:269–71. ated with muscle hypertrophy). The muscle 3 Kung AW, Ma JT, Yu YL, et al. Myopathy in acute disorders usually occur in the setting of an hypothyroidism. Postgrad Med J 1987;63:661–3. 4 Rodolico C, Toscano A, Benvenga S, et al. Myopathy as the established chronic hypothyroid state, though persistently isolated symptomatology of primary autoimmune hypothyroidism. Thyroid 1998;8:1033–8. rarely, they may occur in acute hypothyroidism 5RuVRL, Weissmann J. Endocrine myopathies. 3 Neurol Clin as well. 1988;6:575–92. Myopathy as the sole presenting feature of 6 McKeran RO, Slavin G, Ward P, et al. Hypothyroid myopathy: a clinical and pathological study. J Pathol hypothyroidism, without the other typical signs 1980;132:35–54.