From Confusion to Coma: a Catastrophic Deterioration

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52 Postgrad Med J 2001;77:52–55 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from SELF ASSESSMENT QUESTIONS

From confusion to coma: a catastrophic deterioration

K Ashkan, F Johnston

Answers on p 56. A previously well 45 year old woman presented ventilated before transfer. On arrival at the to the local casualty department with a one day neurosurgical intensive care unit, she was history of generalised headache, neck stiVness, found to have bilaterally fixed and dilated and blurred vision. On examination she had a pupils, with no corneal or gag reflexes. There temperature of 38°C, a pulse of 80 beats/min, was, however, abnormal flexion of the left and a blood pressure of 130/80 mm Hg. Neu- upper limb. She was given mannitol and urgent rologically, she had spontaneous eye opening repeat CT was carried out (fig 2). An operation and was able to obey commands, although she was then performed, but postoperatively she had confused speech (Glasgow coma scale failed to show any clinical improvement and (GCS), 14). Pupils were equal and reactive died the next day. with no cranial or peripheral neurological deficits. Blood tests showed a raised white cell Questions count of 20.9 × 109/l with a neutrophilia (1) What does figure 1 show and what is the (19.2 × 109/l). Computed tomography (CT) of diVerential diagnosis? the brain was performed (fig 1), on the basis of (2) How does figure 2 relate to the change in which the patient was referred to the regional the patient’s clinical condition? neurosurgical unit. While awaiting urgent (3) Discuss the management of this condi- transfer, however, her clinical condition sud- tion. denly deteriorated. There was no eye opening or verbal response, although she flexed to pain- ful stimuli (GCS 5). She was intubated and http://pmj.bmj.com/

Department of Neurosurgery, Atkinson Morley’s Hospital, Copse Hill, Wimbledon, London SW20 0NE, UK K Ashkan F Johnston on September 30, 2021 by guest. Protected copyright.

Correspondence to: Mr Keyoumars Ashkan, Department of Neurosurgery, Hurstwood Park Neurological Centre, Princess Royal Hospital, Haywards Heath, West Sussex RH16 4EX, UK

Submitted 7 October 1999 Figure 1 Computed tomography of the brain at the initial Figure 2 Computed tomography of the brain following the Accepted 20 December 1999 presentation. sudden deterioration.

www.postgradmedj.com Self assessment questions 53 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from Cyanosis in late teens

S G Williams, D J Wright, U M Sivananthan

Answers on p 56. An 18 year old youth presented with a three year history of decreasing exercise tolerance and cyanosis. Physical examination revealed clubbing and cyanosis, with an estimated oxygen saturation of 76% (on air). There were no other abnormalities on cardiovascular or respiratory examination. Arterial blood gas Institute for Cardiovascular estimation revealed a PO2 of 5.85 kPa breathing Research, Yorkshire air, increasing only to 6.8 kPa after 10 minutes Heart Centre, Jubilee on 100% oxygen. Haemoglobin was 22 g/dl. Building, Leeds ECG, chest x ray, and conventional echo- General Inﬁrmary, Leeds LS1 3EX, UK cardiography were normal. S G Williams A transoesophageal echocardiogram is D J Wright shown in ﬁg 1. Figure 1 Transoesophageal echocardiogram. Ao, aorta; U M Sivananthan LA, left atrium; MPA, main pulmonary artery; RPA, right pulmonary artery. Correspondence to: Questions Dr Williams (1) What is the most likely cause of the cya- [email protected] nosis? Submitted 5 November 1999 (2) What does the transoesophageal (3) What treatment options are available for Accepted 31 January 2000 echocardiogram show? this patient?

Recent onset of bleeding and gross coagulopathy

R E Hough, M Makris http://pmj.bmj.com/

Answers on p 57. A 58 year old unemployed man was admitted Clinical chemistry—creatinine 113 µmol/l, as an emergency with a two week history of glucose 5.0 mmol/l, adjusted calcium 2.35 gum bleeding and a one day history of gross mmol/l, aspartate transaminase 17 U/l, alanine haematuria. Other than osteoporosis and low transaminase 18 U/l, bilirubin 5 µmol/l, ã back pain his past medical history was glutamyl transferase 45 U/l, albumin 39 g/l. unremarkable. He had had previous dental

extractions and major surgery without any on September 30, 2021 by guest. Protected copyright. excessive bleeding. He did not have a family Coagulation tests: history of a bleeding disorder. His diet was + Prothrombin time 230 s (normal range normal and contained vegetables and fruit. His 9.5–11.5 s). weight was stable, his appetite was good, and + International normalised ratio (INR) 25.5. he had no bowel symptoms. Regular drug + Prothrombin time + 50% normal plasma ingestion was conﬁned to co-codamol, Distal- 9.5 s. Department of Haematology, gesic, and diazepam. His alcohol intake was + Activated partial thromboplastin time Royal Hallamshire less than 10 units/week. Clinical examination (APTT) 116 s (normal 27–36). Hospital, was unremarkable and he had no purpura or + APTT + 50% normal plasma 49.3 s. Glossop Road, echymoses, no hepatosplenomegaly, and no + Thrombin time 18.6 s (normal 18–23). SheYeld S10 2JF, UK signs of chronic liver disease. R E Hough + Fibrinogen 7.7 g/dl (normal 1.7–3.3). M Makris INVESTIGATIONS Correspondence to: His blood test results on admission were as fol- Questions Dr Makris lows: (1) What is the diVerential diagnosis? [email protected] Full blood count—haemoglobin 14.7 g/dl, (2) What is the most likely diagnosis and how 9 Submitted 28 October 1999 white cell count 12.5 × 10 /l, platelet count would you prove it? Accepted 22 December 1999 222 × 109/l. (3) How would you treat this patient?

www.postgradmedj.com 54 Self assessment questions Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from A young man with seizures, abusive behaviour, and drowsiness

A G Unnikrishnan, S Rajaratnam

Answers on p 58. A 20 year old man was brought to hospital with progressive drowsiness and vomiting for three days. Two weeks before admission his relatives noted that he was becoming agitated, violent, and abusive. He had previously fractured his left humerus owing to a fall during a seizure. He had been on phenytoin and phenobarbitone for seizure control for the past two months. There was no history of substance abuse or alcohol intake, neither was there a history of previous neck surgery. On examination he was dehydrated and he had a tachycardia, a low blood pressure (90/70 mm Hg), and low central venous pressure (+4 cm). He was found to be talking irrelevantly and not obeying commands. He had generalised rigidity. There was no papilloedema. Systemic examination revealed no other abnor- Department of mality. Figure 1 Computed tomography of the brain. Endocrinology, CMC Haematological investigations were normal. Hospital, Vellore—632 Serum biochemical investigation results were parenchymal lesions. Computed tomography 004, Tamil Nadu, India as follows (mmol/l unless stated): sodium 130, of the brain is shown in ﬁg 1. A G Unnikrishnan potassium 3.6, bicarbonate 13, chloride 105, S Rajaratnam magnesium 0.53, calcium 1.025 (corrected Questions Correspondence to: calcium 1.36), phosphorus 1.81, albumin 23 (1) What is the diagnosis? Dr Rajaratnam g/l, urea nitrogen 38.1, creatinine 318 µmol/l, (2) What factors could have worsened the [email protected] and intact parathormone (PTH) 2.1 pmol/l hypocalcaemia in this patient? Submitted 26 October 1999 (normal 1.3 to 7.6 pmol/l). Ultrasound of the (3) What is the diVerential diagnosis on the Accepted 22 December 1999 abdomen showed normal sized kidneys with no computed tomograph of the brain? http://pmj.bmj.com/

A case of reversible amnesia

J Stone, I W Campbell, G D Moran, C J Mumford on September 30, 2021 by guest. Protected copyright.

Answers on p 59. A 43 year old, normally healthy woman was days of intravenous acyclovir for a presumed admitted to a general medical ward after generalised seizure possibly complicating viral Department of Clinical collapsing at home. Over the preceding two encephalitis. Subsequently, CSF and serum Neurosciences, weeks, her husband had noticed that she had viral serology and an autoantibody screen were Western General Hospital, Edinburgh seemed distracted, unusually depressed, and negative. EH4 2XU, UK “not herself.” He had found his wife unrespon- During and after treatment she had a fluctu- J Stone sive and writhing on the floor. She was initially ating level of confusion and appeared distant G D Moran drowsy after the attack but became alert within with a flat aVect. Three weeks after the initial C J Mumford 30 minutes. On admission, she was amnesic for presentation she had another episode of the episode, disoriented in time, place, and collapse with writhing movements as before. Department of Medicine, Victoria person, apyrexial, and clinically euthyroid, with Her mini-mental state examination was 19/30, Hospital, Kirkcaldy no meningism or focal neurological signs. with deficits in orientation and attention and and Department of Computed tomography of the head was total anterograde amnesia. Her neurological Medical Sciences, normal. CSF protein was 0.74 g/l (normal examination remained otherwise normal. She University of range 0.35–0.45 g/l), with normal glucose and was still clinically euthyroid. Her TSH had St Andrews, Fife, UK I W Campbell no cells. Serum biochemistry and full blood increased to 25 mU/l with a normal T4 of 15 count were within normal limits, apart from pmol/l. Her thyroid microsomal antibodies Correspondence to: her thyroid stimulating hormone (TSH) which were raised at more than 1:6400. Her thyro- Dr Stone was raised at 7.14 mU/l (normal 0.5–3.9 globulin antibodies were negative. Magnetic Submitted 19 November 1999 mU/l). Her serum free T4 was normal at 15 resonance imaging of the head was normal. Accepted 10 January 2000 pmol/l (normal 10–19 pmol/l). She received 10 Repeat CSF protein was 0.76 g/l with a normal

www.postgradmedj.com Self assessment questions 55 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from glucose, 4 white cells per high power ﬁeld, and recall feeling mildly depressed and apathetic no oligoclonal bands. An EEG was normal for a week before that. Nine months later she even in the presence of choreiform movements remained well on prednisolone 7.5 mg/day. of the arms. Three days after the second collapse she was Questions started on prednisolone 60 mg daily. Within 24 (1) What is the most likely diagnosis? hours the patient’s mental state returned to (2) Name four other ways in which this dis- normal. She had complete retrograde amnesia ease can present. for the previous four weeks but was able to (3) What is the likely prognosis?

A metabolic complication of pregnancy

S Shah, D Turner, O Adeyemi, S Olczak

Answers on p 60. A 32 year old pregnant woman (gravida 3, para attributed to her pregnancy. There was no his- 1) was referred to the antenatal booking clinic tory of abdominal pain, renal colic, muscle at 12 weeks. She had recently been found to be cramps, arthralgia, or polyuria and she was not hypertensive by her general practitioner, and taking any drugs apart from methyldopa. her blood pressure was 150/100 mm Hg. There was no family history of endocrine Treatment was started with methyldopa. Ultra- disease. Her mother suVered from hyper- sound showed a normally grown fetus. A renal tension, and the patient herself had been ultrasound examination was abnormal (ﬁg1). hypertensive during the last few weeks of her She had symptoms of tiredness and nausea previous pregnancy in 1994. This resolved following delivery. Full blood count, renal function, urate, thyroid function, serum magnesium, and urine microscopy were normal. Serum calcium was 3.47 mmol/l (normal 2.0–2.6 mmol/l), serum Department of phosphate 0.64 mmol/l (0.8–1.2 mmol/l), and Diabetes and serum parathormone 15 ng/l (2–6 ng/l); 24 Endocrinology, University Hospital, hour urinary catecholamine excretion was nor- Nottingham NG7 2UH, mal. Ultrasound of the parathyroids is shown in UK ﬁg 2.

S Shah http://pmj.bmj.com/ Questions Department of (1) What are the ﬁndings on the ultrasound Diabetes and Endocrinology, in ﬁgs 1 and 2? Pilgrim Hospital, (2) How should this patient be managed? Boston, Lincolnshire, UK S Olczak on September 30, 2021 by guest. Protected copyright. Department of Obstetrics and Gynaecology, Pilgrim Hospital O Adeyemi

Department of Surgery, Pilgrim Hospital D Turner

Correspondence to: Dr Shah [email protected]

Submitted 8 December 1999 Accepted 31 January 2000 Figure 1 Renal ultrasound examination. Figure 2 Parathyroid ultrasound examination.

www.postgradmedj.com 56 Postgrad Med J 2001;77:56–61 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from SELF ASSESSMENT ANSWERS

From confusion to coma: a catastrophic aspirate are available. The optimum duration deterioration of antibiotic treatment is not clear but most recommend at least six weeks.2 Q1: What does figure 1 show and what is In the case described here, the patient the diVerential diagnosis? already had severe neurological compromise Figure 1 (p 52) shows a ring enhancing lesion with fixed and dilated pupils by the time of with surrounding oedema in the left frontal arrival at the neurosurgical unit. An urgent lobe. Given the clinical features of pyrexia and stereotactic aspiration of the abscess was also the raised white cell count, the most likely performed and an external ventricular drain diagnosis is cerebral abscess. Other conditions was inserted to allow drainage of infected CSF. to consider in the diVerential diagnosis include Gram stain of the aspirate from the abscess primary and secondary neoplasms. showed both Gram positive cocci and rods. The patient was started on a combination of Q2: How does figure 2 relate to the intravenous benzylpenicillin, cefotaxime, van- change in the patient’s clinical condition? comycin, and metronidazole, as well as intra- Figure 2 (p 52) shows the abscess communi- thecal vancomycin. Despite this treatment, cating and discharging, through a tract, into the however, the patient continued to deteriorate ipselateral ventricle. Intraventricular rupture of and died shortly after. CSF culture results later an abscess is usually a catastrophic event lead- showed Streptococcus milleri and Actinomyces ing to ventriculitis and dissemination of organ- meyeri, both sensitive to penicillin. isms throughout the cerebrospinal fluid pathway.1 This event accounts for the calamitous Conclusion deterioration in the patient’s clinical condition. Proximity of an intracerebral abscess to the ventricular system warrants particularly urgent Q3: Discuss the management of this neurosurgical attention. condition. Improvements in imaging techniques, particu- Final diagnosis larly the development of contrast enhanced CT Intraventricular rupture of cerebral abscess. scanning and its recommended use before lumbar puncture in patients with meningism, 1 Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis advances in neurosurgery and especially stereo- 1997;25:763–81. 2 Zeidman SM, Geisler FH, Olivi A. Intraventricular rupture taxy, availability of more eVective antibiotics, of a purulent brain abscess: case report. Neurosurgery 1995; and better neurointensive care facilities have 36:189–93. 3 Hashizume A, Kodama Y, Hotta T, et al. A case of brain resulted in a substantial reduction in mortality abscess of the basal ganglia which resulted in disastrous out- from brain abscess.1 Intraventricular rupture of come due to ventricular rupture. No Shinkei Geka 1994;22:

383–6. http://pmj.bmj.com/ a cerebral abscess, however, continues to be a 4 Sato M, Oikawa T, Sasaki T, et al. Brain abscess ruptured devastating event, carrying mortality rates of into the lateral ventricle: the usefulness of treatment by 2–4 intraventricular irrigation with antibiotics. A case report. No up to 85%. Shinkei Geka 1994;22:689–93. Delay in diagnosis and subsequent neurosur- 5 Isono M, Wakabayashi Y, Nakano T, et al. Treatment of brain abscess associated with ventricular rupture—three gical referral are important risk factors for this case reports. Neurologia Medico-Chirurgica 1997;37:630–6. condition. The main diagnostic problem is dif- ferentiation of a cerebral abscess from a ring enhancing tumour. Although not absolute, on September 30, 2021 by guest. Protected copyright. however, certain features may favour the Cyanosis in late teens former diagnosis: Abscesses tend to be sited in the vascular watershed regions, often having a Q1: What is the most likely cause of the thin, smooth, enhancing wall which is in cyanosis? contrast to the thick, irregular, diVuse enhance- A form of congenital cyanotic heart disease ment seen with tumours.1 Once suspected, all with a right to left shunt is the most likely cause abscesses require urgent neurosurgical assess- of cyanosis in this case. Pulmonary causes for ment, but perhaps the urgency is greater in the cyanosis are virtually eliminated by the those located close to the ventricular system normal chest x ray and non-correction of because of the risk of intraventricular rupture. hypoxia with 100% oxygen. Once ruptured, the prognosis of such patients remains poor. Both stereotactic aspira- Q2: What does the transoesophageal tion and craniotomy and evacuation of the echocardiogram show? abscess, with variable results, have been The TOE shows an abnormal connection reported.25Most neurosurgeons also advocate (indicated by the arrow) between the left insertion of an external ventricular drain to atrium and dilated right pulmonary artery. The allow both drainage of contaminated cerebro- cause of this patient’s cyanosis is a left atrial to spinal fluid and direct administration of right pulmonary artery fistula. intrathecal antibiotics.24 The choice of antibiotics is crucial and often entails initial treat- Q3: What treatment options are available ment with broad spectrum antibiotics followed for this patient? by more specific antimicrobial treatment once Several treatment options are available. Sur- culture and sensitivity results from the abscess gery can be undertaken to close the fistula by

www.postgradmedj.com Self assessment answers 57 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from ligation or dissection, or it can be closed during cardiac catheterisation and pulmonary angio- Learning points graphy by embolisation using a steel coil, + Cardiac cyanosis (from a right to left umbrella, or detachable balloon. shunt) can be diVerentiated from pulmonary causes of cyanosis by the fact Discussion that there is no significant increase in O A fistula between the pulmonary artery and left P 2 with 100% oxygen. atrium is a rare type of pulmonary arterio- + Pulmonary arterio-venous malforma- venous malformation. It is, however, an impor- tions are relatively common causes of tant diagnosis to make as it can be corrected by cyanosis in adolescence. simple surgical techniques, and the patient + Pulmonary artery to atrial fistula is a usually recovers to lead a normal life. The rare type of pulmonary arterio-venous commonest causes of a pulmonary arterio- malformation. venous malformation are either that it is a con- + The diagnosis of these lesions is impor- genital malformation or that it is associated tant as they are easily treatable. with hereditary haemorrhagic telangiectasia.1 + Conventional echocardiography can Acquired forms are either caused by trauma or miss the diagnosis, and TOE may be are associated with juvenile hepatic cirrhosis, used as a supplementary investigation. portal vein thrombosis, schistosomiasis, or metastatic thyroid carcinoma. Pulmonary arterio-venous malformations usually present in early adult life with the classic triad of considered supplementary investigations. TOE cyanosis, clubbing, and polycythaemia with no has an advantage over computed tomography cardiac murmur. In severe cases they occasion- and angiography, especially in children and ally present with cyanosis and heart failure in adolescents, in that it involves no ionising infancy. A few patients remain completely radiation and is therefore safe for repeated use. asymptomatic—mild desaturation by pulse oximetry may be the only finding. Pulmonary symptoms include breathlessness on exertion, 1 White RI, Lynch-Nyhan A, Terry P, et al. Pulmonary haemoptysis, or thoracic pain. In some pa- arteriovenous malformations: techniques and long term outcome of embolotherapy. Radiology 1988;169:663–9. tients, neurological symptoms such as head- 2 Gelfand MS, Stephen DS, Howell E, et al. Brain abscess: aches, fits, speech disorders, or transient association with pulmonary arteriovenous fistula and hereditary haemorrhagic telangiectasia—report of three ischaemic attacks may dominate the clinical cases. Am Med J 1988;85:718–20. picture. Transient ischaemic attacks and stroke 3 Jimenez M, Fournier A, Chossat A. Pulmonary artery to the from paradoxical emboli may occur in up to left atrium fistula as an unusual case of cyanosis in the new- 1 born. Pediatr Cardiol 1989;10:216–20. 40–50% of patients. It is estimated that the 4 Chilvers ER. Clinical and physiological aspects of pulmo- annual risk of stroke in these patients is nary arteriovenous malformations. Br J Hosp Med 1988;196: approximately 1.5%.2 188–92. Cardiac cyanosis (caused by a right to left shunt) is diVerentiated from pulmonary causes http://pmj.bmj.com/ of cyanosis by there being no significant Recent onset of bleeding and gross coagulopathy increase in PO2 after inhaling 100% oxygen. Secondary polycythaemia may occur because of a compensatory increase in erythropoietin Q1: What is the diVerential diagnosis? production. Other simple clues to aid the diag- The diVerential diagnosis is: nosis include ECG findings of left axis + Congenital factor V or factor X deficiency. deviation, left atrial enlargement, and left ven- + Acquired deficiency of factor V or factor X on September 30, 2021 by guest. Protected copyright. tricular hypertrophy,34and an opacity adjacent resulting from a specific autoantibody. to the right border of the cardiac silhouette on + Acquired factor X deficiency in association chest x ray.3 with systemic amyloidosis. To diagnose an atrial to pulmonary artery + Vitamin K deficiency. fistula, a high index of suspicion is required + Warfarin overdose/excess. during echocardiography. The pulmonary ar- In view of the extreme prolongation of tery may appear dilated and tortuous, and prothrombin time and APTT, if this was factor increased flow velocities may be seen on Dop- V or factor X deficiency, it would have to have pler examination of the pulmonary veins. This been a severe deficiency with clotting factor is often diYcult to detect, especially in smaller levels less than 2% of normal. The fact that he shunts, and this diYculty was seen in our case. had had previous surgery without excessive TOE can be used as a supplementary investigation and has proved to be of great diagnostic bleeding eVectively excludes congenital defi- value in many aspects of both paediatric and ciency of these factors. Acquired deficiency adult cardiology. Convention transthoracic caused by an autoantibody specifically against echocardiography is limited by the poor tissue factors V or X is also excluded by the fact that penetration of high frequency transducers (5 there was normalisation of the clotting tests in MHz). Adequate images can be sometimes dif- the mixing experiments. In a previously healthy ficult to obtain even with lower frequency man amyloidosis would be unlikely. The high transducers (2.25–2.5 MHz), and structures at fibrinogen and normal platelet count, in the the back of the heart (for example, the left presence of such prolonged prothrombin time, atrium) can often be missed. Magnetic reso- makes the diagnosis of liver disease or dissemi- nance imaging and computed tomography are nated intravascular coagulation highly unlikely.

www.postgradmedj.com 58 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from Q2: What is the most likely diagnosis and how would you prove it? Learning points The most likely cause would be a problem with + A good history will diVerentiate between the vitamin K dependent clotting factors, inherited and acquired coagulation either because of vitamin K antagonism abnormalities. (warfarin excess) or because of vitamin K defi- + Mixing experiments will diVerentiate ciency (dietary deficiency or malabsorption). between a true deficiency and the Vitamin K deficiency would be extremely presence of an inhibitor. unlikely in view of the patient’s normal diet and + Warfarin can be demonstrated in plasma lack of gastrointestinal symptoms, and as he directly using high performance liquid had not been taking any antibiotics. Although chromatography. This is useful in we normally detect the warfarin eVect indi- detecting warfarin in patients who deny rectly by its action on the coagulation system taking the drug, or more often where (by measuring the INR), it can also be demon- patients who are meant to be on warfarin strated directly in the patient’s plasma, using present with normal clotting and claim to high performance liquid chromatography be taking their tablets. (HPLC). + In patients with very high INR, fresh frozen plasma is not required. Q3: How would you treat this patient? Intravenous vitamin K will correct the As the bleeding is not life threatening, coagulopathy within 6–8 hours. treatment with intravenous vitamin K is all that is required. dose of vitamin K, as this would correct any

OUTCOME IN THIS PATIENT anticoagulant related problem. Ten hours after an intravenous dose of 10 mg This was an unusual case in that the patient vitamin K, his bleeding stopped, his pro- inadvertently received warfarin. Clinically the thrombin time was 15.9 s and his APTT was situation most commonly encountered when 37.9 s. By the following day all his clotting tests patients have a similar coagulopathy is either a were normal. Although he denied taking any deliberate overdose with warfarin or a drug warfarin, this drug was detected in his plasma interaction in patients who are already taking using HPLC. When his regular drugs were warfarin. In all such situations it is tempting to examined, the container with a label of use fresh frozen plasma to replace the clotting diazepam contained 5 mg warfarin tablets. factors; 1 litre of plasma will, however, only raise the individual factor levels by 10%.2 A much Discussion more eVective way is to give intravenous vitamin When faced with significantly abnormal coagu- K, which will bring the INR into the therapeutic lation tests, as in this case, the clinician must range in almost all cases within six to eight first decide if the abnormality is likely to be hours. The dose of vitamin K will depend on inherited or acquired. For patients who have whether anticoagulation needs to be continued, had haemostatic challenges in the past—such as for example in patients with metal prosthetic http://pmj.bmj.com/ as surgery or dental extractions—without heart valves, when a dose of 2–3 mg should be excessive bleeding, this is usually easy. In given and repeated if necessary. For patients in inherited deficiencies the only reliable way to whom anticoagulation will not be continued, a make the diagnosis is by direct measurement of dose of 10 mg should be given. the relevant individual clotting factors. 1 Hay CRM, Colvin BT, Ludlam CA, et al. Recommendations The next step in a case of an acquired for the treatment of factor VIII inhibitors: from the UK abnormality such as this is to see if the defect is Haemophilia Centre Directors’ Organisation Inhibitor Working Party. Blood Coagul Fibrinolysis 1996;7:134–8. on September 30, 2021 by guest. Protected copyright. caused by a true synthetic deficiency or by 2 Makris M, Greaves M, Phillips WS, et al. Emergency oral destruction of the synthesised clotting factor by anticoagulant reversal: the relative eYcacy of infusions of fresh frozen plasma and clotting factor concentrate on cor- a specific autoantibody against it. Factor VIII rection of the coagulopathy. Thromb Haemost 1997;77:477– autoantibodies causing acquired haemophilia 80. A are the ones most commonly encountered in clinical practice, but autoantibodies to all the clotting factors have been reported. These two A young man with seizures, abusive possibilities can be diVerentiated by perform- behaviour, and drowsiness ing mixing tests.1 Patient’s plasma is mixed with normal plasma that contains all the Q1: What is the diagnosis? clotting factors in normal amounts. If an anti- The diagnosis is idiopathic hypoparathy- body is present, it will destroy the added factor roidism with basal ganglia calcification. The and the clotting tests will remain prolonged. In serum PTH level is inappropriately low for the a true synthetic deficiency the addition of the degree of hypocalcaemia. Hypocalcaemia factor in plasma will correct the clotting tests. could have been worsened by other factors (as When both the PT and APTT are abnormal, mentioned below). the problem is either a single factor deficiency There was associated renal failure, probably in the common coagulation cascade pathway, from prerenal causes, as the patient was or it is caused by defects in both the intrinsic clinically dehydrated and hypotensive, with a and the extrinsic pathways; these are mostly a low central venous pressure and a high urea to result of oral anticoagulant therapy. Although creatinine ratio. Renal ultrasound was normal. all the coagulation factors can be assayed indi- Chronic renal failure with secondary hyper- vidually, a more practical step is to give a single parathyroidism can be a cause of basal ganglia

www.postgradmedj.com Self assessment answers 59 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from calcification,1 but there would be high circulating parathormone in that case. Box 1: Causes of basal ganglia Basal ganglia calcification is known to be calcification associated with calcification of the cortex and + Idiopathic basal ganglia calcification cerebellum.2 In such cases the patient can + Hypoparathyroidism present with neuropsychiatric manifestations.3 Idiopathic (autoimmune) Congenital Q2: What factors could have worsened Post-thyroidectomy the hypocalcaemia in this patient? + Pseudohypoparathyroidism Other factors that could have contributed to + Secondary hyperparathyroidism (in the hypocalcaemia include hypomagnesaemia, renal disease ) renal failure, and the use of anticonvulsant + Congenital infections (for example, drugs. Hypomagnesaemia produces hypocal- toxoplasmosis ) caemia by reducing parathormone secretion + Mitochondrial cytopathies and also by interfering with parathormone + Fahr syndrome action.4 Hypomagnesaemia in our patient was + Cockayne syndrome probably caused by a combination of an inad- + Toxins equate intake and acidosis from the accompa- Carbon monoxide nying renal failure. Systemic acidosis is known Lead poisoning to aggravate magnesium loss in the urine. High dose calcium replacement can lead to calciuria and renal magnesium wasting; hence the serum magnesium in hypoparathyroid patients on Learning points treatment needs to be monitored closely. + Basal ganglia calcification may present Phenytoin and phenobarbitone can interfere with neuropsychiatric manifestations. with vitamin D metabolism.5 These drugs + Calcific foci in other intracranial sites induce hepatic enzymes that convert vitamin D like the cerebellum and cerebral cortex and 25-hydroxyvitamin D into their inactive are often associated features. metabolites. In addition they impair calcium + Magnesium deficiency can worsen absorption from the gut and also aVect the hypocalcaemia. resorption of calcium from bone. + Frequent estimation of serum magne- Low albumin may reduce the total serum sium is necessary in patients on treat- calcium but it does not aVect the ionised ment for hypoparathyroidism. calcium levels and hence does not contribute to + If these patients also require long term symptomatic hypocalcaemia. anticonvulsant treatment, they will need close monitoring of their calcium status. Q3: What is the diVerential diagnosis on the computed tomograph of the brain? The various causes of basal ganglia calcifica- levadopa with carbidopa was suYcient to tion are listed in box 1. The most important control the extrapyramidal symptoms. He was http://pmj.bmj.com/ treatable cause is hypoparathyroidism. This is asymptomatic and normocalcaemic on dis- characterised by hypocalcaemia, hyperphos- charge. phataemia, and a low serum parathormone. Idiopathic hypoparathyroidism can occur as an Final diagnosis isolated condition or it may be part of a poly- Idiopathic hypoparathyroidism with basal gan- glandular endocrinopathy (candidiasis, au- glia calcification toimmune hypoadrenalism, and thyroid dis- on September 30, 2021 by guest. Protected copyright. ease). Pseudohypoparathyroidism is caused by 1 Sutton D, Kendall B, Stevens J. Intracranial lesions. In: Sut- target organ resistance to parathormone. These ton D, ed. Textbook of radiology and imaging, 6th ed. New York: Churchill Livingstone, 1998:1619–60. patients have characteristic clinical features 2 Goel A, Bhatnagar MK, Vashishta A, et al. Hypoparathy- (such as a short fourth metacarpal bone) and roidism with extensive intracranial calcification: a case report. Postgrad Med J 1994;70:913–15. high circulating parathormone levels. 3 Rosenberg DR, Neylan TC, El-Alwar M, et al. Neuropsychi- Idiopathic basal ganglia calcification can atric symptoms associated with idiopathic calcification of the basal ganglia. JNervMentDis1991;179:48–9. occur as a normal variant in elderly people. 4 Becker KL. Principles and practice of endocrinology and Other causes include Fahr syndrome (idio- metabolism. Philadelphia: JB Lippincott, 1995:559–622. 5 Hahn TJ. Drug induced disorders of vitamin D and mineral pathic cerebrovascular ferrocalcinosis) and metabolism. Endocrinol Metab Clin North Am 1980;9:107– Cockayne syndrome (associated with prog- 29. eria). Basal ganglia calcification can also result from exposure to lead and carbon monoxide. A case of reversible amnesia PROGRESS OF OUR PATIENT The patient was started on an intravenous Q1: What is the most likely diagnosis? calcium infusion. He was also given parenteral The combination of delirium, intermittent magnesium sulphate. His sensorium improved neurological symptoms, high CSF protein, dramatically and he was started on oral calcium normal MRI, positive antithyroid antibodies, and vitamin D supplements. His renal function and reversibility of symptoms with steroids is improved with adequate hydration, and his highly suggestive of Hashimoto’s encephalopa- serum creatinine and urea levels normalised. thy. The diVerential diagnosis of delirium with This confirmed our suspicion that there was a normal MRI includes systemic infection, viral underlying prerenal failure. A small dose of or other infective causes of encephalitis, meta-

www.postgradmedj.com 60 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from bolic disturbance (including hypothyroidism and hyperthyroidism), drug intoxication or Learning points withdrawal, or non-convulsive status epilepti- + Hashimoto’s encephalopathy is an cus (or postictal or interictal confusion). increasingly recognised cause of a wide Rarely, autoimmune disorders such as systemic variety of potentially serious neurologi- lupus erythematosus or primary central nerv- cal symptoms that usually respond dra- ous system vasculitis, and primary CNS matically to steroids. tumours such as intravascular lymphoma, may + Patients are mostly clinically euthyroid present with a normal MRI. in the presence of high titres of serum thyroid autoantibody. Q2: Name four other ways in which this + MRI of the head is usually normal but disease can present. CSF protein is often raised. There is The manifestations of Hashimoto’s encepha- sometimes a CSF pleocytosis lopathy are protean, encompassing virtually any + Caution must be exercised in keeping a neurological symptom. In a recent survey of low threshold for the diagnosis but also reported cases,1 the frequency of symptoms was in not overdiagnosing the condition as follows: epileptic seizures 63%, reduced con- + Always check serum thyroid sciousness 54%, dementia 52%, psychosis 48%, autoantibodies in patients with undiag- personality change 39%, myoclonus 33%, ataxia nosed delirium. 28%, pyramidal signs 28%, stroke-like episodes 26%, hallucinations 19%, extrapyramidal move- ment disorder 7%, dysarthria 7%. sive encephalopathy should be taken into Q3: What is the likely prognosis? account. This has not been definitively studied. Many The pathogenesis is unknown. Most cases either respond dramatically to steroids or investigators1–3 assume the presence of a cross resolve spontaneously. Untreated, the condition reacting antigen in the central nervous system, can develop into a severe dementia with neuro- perhaps producing an immune complex medi- 1 logical features. A recent report describes seven ated vasculitis. Corticosteroids are the treat- cases that were initially diagnosed as ment of choice. Prednisolone doses of over 60 Creutzfeldt-Jakob disease but subsequently im- mg are usually used, although intravenous proved or resolved after corticosteroid treat- methylprednisolone and immunosuppressants ment. such as azathioprine and methotrexate have also been employed successfully. Discussion Hashimoto’s encephalopathy is not yet Brain et al first observed the association widely known, and may be an underdiagnosed between encephalopathy and autoimmune thy- 2 cause of acute confusion in the general medical roid disease in 1966. After a report of two ward. Given its protean manifestations and cases,3 and the first case series,4 the condition

reversibility with treatment, a low threshold of http://pmj.bmj.com/ was increasingly recognised in the last decade.1 suspicion is important. Thyroid autoantibodies The mean age of onset is 41 years (range 14 to should always be checked in cases of confusion 78), with a female to male preponderance of where the diagnosis is not clear. 5.6:1. The hallmarks of the condition are: + An encephalopathy presenting as delirium or dementia, usually with neurological signs Final diagnosis or seizures as listed above. Hashimoto’s encephalopathy + Raised serum titres of thyroid microsomal or on September 30, 2021 by guest. Protected copyright. thyroglobulin antibody, usually in clinically 1 Seipelt M, Zerr I, Nau R, et al. Hashimoto’s encephalitis as euthyroid patients, but hypothyroid and adiVerential diagnosis of Creutzfeldt-Jakob disease. J Neu- rol Neurosurg Psychiatry 1999;66:172–6. hyperthyroid cases are reported. 2 Brain L, Jellinek EH, Ball K. Hashimoto’s disease and + Usually steroid responsive, often dramati- encephalopathy. Lancet 1966;ii:512–14. 3 Thrush DC, Boddie HG. Episodic encephalopathy associ- cally so. ated with thyroid disorders. J Neurol Neurosurg Psychiatry Depression and anxiety are common early 1974;37:696–700. 4 Shaw PJ, Walls TJ, Newman PK, et al. Hashimoto’s symptoms, but psychosis and personality change encephalopathy: a steroid-responsive disorder associated can also be presenting features. Brain imaging is with high anti-thyroid antibody titers; report of 5 cases. usually normal although MRI can show high Neurology 1991;41:228–33. 5 Bohnen NI, Parnell KJ, Harper CM. Reversible MRI signal lesions on T2 weighted images in the findings in a patient with Hashimoto’s encephalopathy. Neu- subcortical white matter.5 Cerebrospinal fluid rology 1997;49:246–7. protein is raised in 65% of cases and 15% have a CSF pleocytosis (maximum 169 leucocytes/ mm3). Thyroid autoantibodies must be raised to A metabolic complication of pregnancy make the diagnosis, although it must be remem- bered that these are raised in 3–4% of the popu- Q1: What are the findings on the lation. Some investigators also suggest ultra- ultrasound in figs 1 and 2? sonography of the thyroid to detect a hypoechoic The ultrasound image of the kidneys (fig 1; pattern.5 Clearly, with such a wide variety of p 55) shows marked bilateral renal medullary presentations and no definitive tests the diagno- calcification (nephrocalcinosis). The ultra- sis must be made with caution, perhaps only sound image of the parathyroids (p 55) shows a after a careful trial of steroids. Spontaneous parathyroid adenoma with the Doppler signal remissions and other causes of steroid respon- produced by the blood flow to the adenoma.

www.postgradmedj.com Self assessment answers 61 Postgrad Med J: first published as 10.1136/pmj.77.903.53a on 1 January 2001. Downloaded from Q2: How should this patient be managed? This patient should have a parathyroidectomy Learning points during the second trimester. Hyperparathyroidism in pregnancy + Clinical presentation during pregnancy OUTCOME IN THIS CASE is similar to that found in the general The patient’s blood pressure remained well population and it is sometimes diag- controlled on methyldopa and at 20 weeks’ nosed retrospectively following the birth gestation she had the parathyroid adenoma of the baby. removed under general anaesthesia. The diag- + If untreated, it results in a substantial nosis was confirmed on histology. Her serum increase in morbidity and mortality in calcium fell to 2.34 mmol/l postoperatively and the newborn infant. has since remained normal. She gave birth to a + Surgery during second trimester is the normal baby girl at term. Following surgery she treatment of choice. remained normotensive, even after the methyldopa was discontinued. and mortality. None of the medical treatments Discussion presently available is safe in pregnancy. There Hyperparathyroidism during pregnancy is un- have been anecdotal reports of the successful common, with just over 100 cases reported use of oral phosphate.5 Current recommenda- since the first description by Hunter in 1931. tions for the treatment of hyperparathyroidism The incidence is not known; however, in all during pregnancy advocate surgery during the women of child bearing age the annual second trimester.6 Our patient underwent sur- incidence of new cases is said to be about gery without any adverse eVect at 20 weeks. It 8/100 000 population.1 This condition results is prudent to avoid surgery during the first tri- in a 20–30% incidence of fetal or neonatal mester until the completion of organogenesis, death and an incidence of complications and in the third trimester, when there is an during pregnancy exceeding 50% if untreated.2 increased risk of spontaneous labour. There is Physiological adjustment during pregnancy an association of hypertension with hyperpar- maintains calcium homeostasis despite in- athyroidism, the cause of which is unknown. creased requirements (approximately 30 g) for This patient’s hypertension was cured follow- fetal skeletal development. Intact parathor- ing surgery. Nephrocalcinosis is known to mone levels remain largely unchanged or result from primary hyperparathyroidism and diminish during pregnancy.3 Total serum it remains to be seen if it will resolve in this calcium decreases, reflecting a fall in serum patient. albumin. A consistent increase in maternal In conclusion, when hyperparathyroidism is vitamin D3 levels with advancing gestation suspected in pregnancy, eVorts should be made ensures that the fetal requirements for calcium to make an early definitive diagnosis so that are met through increased intestinal absorption surgery can be planned for the second trimes- of calcium.4 The clinical presentation of hyper- ter. In patients with parathyroid adenoma, sur- parathyroidism during pregnancy is similar to gery at this stage is usually associated with suc- http://pmj.bmj.com/ that found in the general population, and many cessful maternal and fetal outcomes. patients are asymptomatic. Untreated primary hyperparathyroidism increases the risk of fetal 1 Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism: incidence, morbidity, and potential economic loss, neonatal morbidity (in particular tetany), impact in a community. N Engl J Med 1980;302:189–93. 2 Ludwig GD. Hyperparathyroidism in relation to pregnancy. N Engl J Med 1962;267:637–43. 3 Davis OK, Hawkins DS, Rubin LP, et al. Serum parathor- Box 1: Causes of nephrocalcinosis mone (PTH) in pregnant women determined by an immu- noradiometric assay for intact PTH. Clin Endocrinol Metab on September 30, 2021 by guest. Protected copyright. + Medullary sponge kidney 1988;67:850–2. + Primary hyperparathyroidism 4 Reddy GS, Norman AW, Willis DM, et al. Regulation of vit Hypercalciuria D metabolism in normal human pregnancy. Clin Endocrinol + Metab 1983;56:363. + Hypervitaminosis D 5 Montoro MN, Collea JV, Mestman J. Management of Sarcoidosis hyperparathyroidism in pregnancy with oral phosphate + therapy. Obstet Gynecol 1980;55:431–4. + Fabry’s disease 6 NIH Consensus Development Conference Statement. Wilson’s disease Diagnosis and management of asymptomatic primary hyperpar- + athyroidism. Bethesda, MD: National Institutes of Health: October 29–31, 1990.