Neurology — Long Cases

12 Neurology—Long Cases Raymond Tak-Fai Cheung, Shu-Leong Ho, Windsor Mak, and Koon-Ho Chan 12.1 Confused speech (embolic stroke due to rheumatic mitral valve disease and atrial fibrillation) History A 35-year-old right-handed woman presented with sudden onset of confused speech and poor communication for 3 days. She was a new immigrant from mainland China to Hong Kong and lived in an apartment in a private housing estate, with her 60-year-old husband and two teenage children from his first marriage. She was brought up in a farming village, had not had any major medical illness in the past, and was a non-smoker and non-drinker. However, her exercise tolerance was not as good as her peers and so she could not perform heavy manual farm work as much as others in her family did. Three days ago, she was found to have confused speech with difficulty in verbal communication. Her husband thought that she had a flu and kept her at home. As there was no improvement, she was brought to the accident and emergency department and then admitted to a medical ward. Before the current episode, she had complained of palpitations especially with exertion, and her ' exercise tolerance was limited to 2 flights of stairs. She was not on oral contraceptive pills. She had no fever, flu-like symptoms, constitutional upset, or motor weakness.

Case 12.1 Neurology 165 Physical examination She was alert, conscious, and afebrile. Her blood pressure was 110/60 mmHg. She had a totally irregular, small volume pulse with a rate of 90 per minute. All peripheral pulses were felt. The apex was not displaced. There was a parasternal heave, but no thrill was detected. On auscultation, the apical rate was 110 per minute, the first heart sound was normal, the pulmonic component of her second heart sound was loud, and two murmurs were heard best at the apex. There was a grade 3/5 pansystolic murmur radi- ating to the axilla, and another grade 3/5 mid-diastolic murmur was louder with her lying in the left lateral position. Neurological examination was difficult, as she failed to understand instructions. Her spontaneous speech and naming of objects appeared normal. Examination of her cranial nerves yielded nothing of note, and muscle bulk, tone, and power in her limbs were entirely normal. Her reflexes were symmetrical; both plantar responses were down- going, coordination was normal, and sensations were intact. All other systems were normal. Questions 1. What are the diagnoses and on what grounds are they made? * Cardiac: mixed mitral valve disease, pulmonary hypertension, and atrial fibrillation. Neurological: Wernicke’s aphasia (posterior part of the left superior temporal gyrus) from a cardioembolic stroke. The history of reduced exercise tolerance, palpitations (atrial fibril- lation), mixed mitral valve disease, and sudden onset of fluent aphasia are all consistent with this diagnosis. 2. What are the supportive physical findings for these diagnoses? * Signs of a cardiac problem include a pansystolic murmur at the apex from mitral regurgitation, a mid-diastolic murmur with postural accentuation from mitral stenosis, atrial fibrillation from irregular pulse and a higher apical rate than peripheral pulse rate, pulmonary hypertension from a parasternal heave, and a loud pulmonic second heart sound.

166 Problem-Based Medical Case Management Case 12.1 . 3. Signs of a stroke affecting Wernicke’s area include fluent aphasia and otherwise normal neurological examination. Clinically how do you determine the severity of mitral ste- nosis versus mitral regurgitation in patients with mixed mitral valve disease? 5. Features of predominant mitral stenosis include: a small volume pulse, an undisplaced tapping cardiac apex, a long diastolic murmur, and signs of pulmonary hypertension. Features of predominant mitral regurgitation include a dis- placed cardiac apex and a palpable systolic thrill. . How would you investigate the patient? Blood tests should include complete blood counts, liver and renal. function tests, coagulation tests, fasting glucose and lipids. Neurologic investigations should include a plain com- puted tomography (CT) brain to show any infarct over the Wernicke’s area and to exclude haemorrhage, tumour, or other lesions. A normal CT is possible, in which case magnetic reso- nance imaging (MRI) stroke package may be more revealing. Cardiologic investigations include assessment of heart size and lung fields on CXR, ECG to document atrial fibrillation, and an echocardiogram to assess mitral stenosis and regurgi- tation, left atrial size, the presence of intra-cardiac thrombus or vegetations on any valves. An MRI stroke package includes brain MRI, brain magnetic resonance angiography (MRA), and neck MRA. What are the potential risks of rheumatic mitral valve disease? Systemic and cerebral embolization, infective endocarditis, systemic and cerebral haemorrhage from long-term anti-coagu- lation, heart failure, and pulmonary hypertension. . How would you treat the patient? The patient will require long-term anti-coagulation and speech therapy. What advice would you give to the patient? She will need advice on diet, drug compliance, and regular monitoring of her long-term anti-coagulation.

Case 12.2 Neurology 167 8. Where is the Wernicke’s area? « It is located at the posterior part of the left superior temporal gyrus. Lesion involving this area will lead to Wernicke’s or receptive aphasia. 9. Would there be any concern about performing an MRI examination if she had received a valvular surgery? « The metallic artificial heart valve may or may not be compatible with MRI examination. Pitfalls and tips * Failure to detect receptive aphasia * Failure to elicit the cardiac signs * Failure to link them together 12.2 Epilepsy with poor seizure control History A 35-year-old narcotic abuser and street-sleeper with an unre- markable past medical history was admitted via the accident and emergency department to a medical ward. He was found unarous- able in a park. The ambulance officer noticed a few twitches in his legs while transporting him. He regained consciousness before arriving at the hospital. Physical examination Physical examination was unremarkable. Investigations He refused blood taking, but urine toxicology showed presence of methadone. Brain CT was normal. Electroencephalography showed a transient run of bilateral frontal sharpish discharges that lasted for 2 seconds.

168 Problem-Based Medical Case Management Case 12.2 Clinical course He was discharged after 7 days of observation. During this period, he remained asymptomatic other than having some non-specific giddiness and headache. Epilepsy was diagnosed in view of the history of loss of consciousness associated with leg twitching and the electroencephalograhic findings. Phenytoin was started. A monthly disability allowance was also approved, though he continued to work as a part-time taxi driver. Subsequently, he was repeatedly admitted to the medical wards via the accident and emergency department for seizures. He claimed that his attacks were precipitated by hunger or bad weather. CT brain, electro- encephalography, and Holter monitoring were performed during some of these admissions, but did not show any abnormalities. The patient always refused blood taking. He had several witnessed seizures during hospitalization, which occurred when he was upset or after quarrelling with the nurses. Sodium valproate, phenobar- bitone, and clonazepam were added on top of phenytoin, but his condition did not improve. In view of poor seizure control, he was referred to the epilepsy clinic for workup of possible surgically amenable epilepsy syndromes. Investigations including magnetic resonance imaging and single photon emission computed tomogra- phy scan were negative. Video-electroencephalographic telemetry failed to detect any events after 14 days of recording. He refused further invasive recordings. His medications were changed to a combination of valproate, lamotrigine, topiramate, and gabapen- tin. He insisted on continuing phenobarbitone and clonazepam, because he thought these drugs “were helping him”, claiming such treatment had improved his condition by 50%. Further information One day, he was arrested for illegal trading of medications at a drugstore. All along he had been selling his supply of valproate, lamotrigine, gabapentin, and topiramate in exchange for cash or methadone. He shared his phenobarbitone and clonazepam with his friends. He and the drugstore pharmacist were found guilty.

Case 12.2 Neurology 169 After release from prison, he still attended the hospital frequently for episodic loss of consciousness. A video-electroencephalo- graphic telemetry was repeated, which documented 18 events over 3 days. Analysis of the recordings showed that they were actually pseudoseizures. All medications as well as the disability allowance were discontinued. After that, he changed his complaint to recur- rent abdominal pain. Questions 1. What are epileptic seizures and epilepsies? * An epileptic seizure is a brief and usually unprovoked stereo- typed disturbance of behaviour, emotion, motor function or sensation, which on clinical evidence results from a cortical neuronal discharge. * Epilepsy is diagnosed when there are recurrent unprovoked seizures. 2. What are the differential diagnoses of epileptic seizures? * Syncope. * Metabolic encephalopathy, e.g., hypoglycaemia, hepatic encephalopathy. * Hyperventilation syndrome. ¢ Drop attacks. * Sleep disorders, e.g., sleep walking, narcolepsy-cataplexy syndrome. * Movement disorders, e.g., tics, hemifacial spasm, startle, choreoathetosis. * Psychiatric conditions, e.g., pseudoseizures, panic attack. Transient global amnesia. Transient ischaemic attacks. 3. How are blood tests relevant to suspected epileptic seizures? To identify/exclude metabolic causes of epileptic seizures. To identify the metabolic consequences of generalized seizures, e.g., raised muscle enzymes, neutrophilia, hyperprolactinaemia. To identify/exclude metabolic encephalopathy. To check anticonvulsant levels.

170 Problem-Based Medical Case Management Case 12.2 5. . What mistakes are illustrated in the clinical course? Inappropriate starting of anti-convulsant after one suspected epileptic seizure. Known narcotic abuser with positive urine test for metha- done, making drug overdose a possible explanation of loss of consciousness. Driving is forbidden especially for people working as drivers. Drug level has not been checked to ensure adequate dosing and compliance prior to add-on therapy. Other than common side effects such as drowsiness, cere- bellar syndrome, and drug interactions, what are the specific side effects of phenytoin, sodium valproate, lamotrigine, and topiramate? . Phenytoin: gum hypertrophy, acne, hirsutism, lupus-like syn- drome, Stevens-Johnson syndrome, agranulocytosis. Sodium valproate: alopecia, tremor, weight gain, dyspepsia, hepatotoxicity, hyperammonaemia, acute pancreatitis. Lamotrigine: skin rash. Topiramate: paraesthesia, anorexia, weight loss. Pitfalls and tips Limb twitching is quite common in non-epileptic conditions that cause impairment of consciousness. An erroneous diagnostic label of epilepsy can have profound consequences. The main purpose of investigating a patient with seizure(s) is to look for an underlying brain lesion or other secondary causes. Epilepsy and seizure are diagnosed by history or clinical obser- vation. The finding of EEG abnormalities is not specific for epilepsy. Non-compliance is a common cause of refractory epilepsy. Pseudoseizure is a common cause of suspected refractory epilepsy. Manipulative behaviour as well as sick role can often be rein- forced by financial gains.

Case 12.3 Neurology 171 + Some anti-convulsants can be used as drugs of abuse. « It is important to know the general and specific side effects of common anti-convulsants. 12.3 Diplopia on reading (myasthenia gravis with thyrotoxicosis) History A 23-year-old woman presented to a private practitioner with a 6-week history of generalized malaise, weight loss of 8 pounds, fine hand tremor, and increased sweating. She was a cashier, and her past health was good. She was single, did not take regular medi- cations, and had no family history of neurological disease. She was diagnosed to have thyrotoxicosis with blood free T4 level raised to 38 U/L and TSH level suppressed to 0.22 U/L. She responded to treatment with carbimazole, which was successfully tailed off after 1 year. However, 9 months later, she noticed increased fatigability of all four limbs and double vision after prolonged reading. She had no dysarthria or dysphagia, but her exercise tolerance dete- riorated from being essentially unlimited to climbing 3 flights of stairs (limited by limb fatigability). Her symptoms were worse in the evening. Physical examination Examination revealed a clinically euthyroid woman with coherent speech and mild right partial ptosis that worsened on prolonged Upward gaze. She complained of diplopia on bilateral horizontal gaze with partial impairment of right eye abduction and left eye adduction noted upon repeated eye movements; pupils were equal and reactive to light. Other cranial nerves were intact. Muscle tone Was normal with grade 4/5 proximal muscle weakness. Tendon reflexes, gait, and sensation were normal, and she had no cerebel- lar signs.

172 Problem-Based Medical Case Management Case 12.3 Investigations Tensilon test (intravenous edrophonium injection) was positive, with marked improvement of ptosis and resolution of diplopia. Serum acetylcholine receptor antibody test was positive. Computed tomography scan of the thorax did not reveal any thymic mass. Repetitive nerve stimulation over her trapezius at 3 Hz revealed a 20% decremental response. Questions 1. After 6 months of mestinon at 30 mg tds, she noticed increased proximal muscle weakness and moderate dysphagia. How do you manage her? * Mestinon dose could be stepped up for an inadequate response. Systemic corticosteroids and steroid sparing drugs, such as azathioprine, were not started due to a concern of potential long-term adverse effects, including risk of lymphoproliferative diseases. 2. What are the non-drug alternatives for myasthenia gravis? * Thymectomy should be advised, and significant improvement in the absence of a thymoma can occur after thymectomy. ¢ Plasmapheresis has been used in intractable cases, but the benefit is temporary. 3. What are the similarities and differences between myasthe- nia gravis and Eaton-Lambert syndrome? Similarities Myasthenia gravis Eaton-Lambert syndrome ¢ Proximal muscle weakness » Easy fatiguability ¢ Neuromuscular junction problem * Absence of sensory features * Respond to anticholinesterase or plasmapheresis

Case 12.3 Neurology 173 Differences Myasthenia gravis Eaton-Lambert syndrome ¢ Qcular, bulbar Common Rare involvement Pathogenesis Post-synaptic, acetylcholine receptor antibody Pre-synaptic, voltage-gated calcium channel antibody * Post-exercise Absent Present (with return potentiation of reflexes) * Repetitive Decremental Decremental at nerve response low frequency, stimulation incremental at high frequency * Associated Thymic Nil thymus hyperplasia, pathologies thymoma * Associated Thymoma Carcinoma of tumour bronchus, ovaries, ete. 4. What are other causes of ptosis and how can they be differentiated? * Third cranial nerve palsy: usually complete ptosis with ophthal- moplegia and dilated unreactive pupil. * Horner’s syndrome: partial ptosis, miotic reactive pupil, anhi- drosis, enophthalmos. Pitfalls and tips * Failure to detect diplopia and easy fatigability * Poor knowledge on neuromuscular junction disorders

174 Problem-Based Medical Case Management Case 12.4 12.4 Tuberculous meningitis complicated by stroke History A 30-year-old lady with swinging fever, night sweats, chills, and rigors for 4 weeks presented acutely with disorientation. She had received in vitro fertilization for primary infertility due to fallopian tube blockage, using human chorionic gonadotrophin. She had premature rupture of her amniotic membrane at 18 weeks of gesta- tion, and was given 2 intravenous injections of betamethasone for fetal lung maturation. Emergency caesarean section was carried out for fetal bradycardia at 29 weeks of gestation. Several days after delivery, her symptoms started. There was no joint pain, skin rash, leg swelling, dysuria, cough, chest or abdominal discomfort, or vaginal bleeding. Physical examination was normal. Empirical broad-spectrum intravenous antibiotics were given. She remained unwell, and her high swinging fever persisted. One month post- partum, she had acute onset of confusion and disorientation, and developed partial drooping of her right eyelid. Her antibiotic regimen was adjusted to cover possible listeriosis. Her condition deteriorated further, and she developed sudden-onset left hemi- paresis. Anti-tuberculous treatment with steroids (dexamethsone) was added empirically to cover tuberculous meningoencephalitis. Aspirin was also added for her stroke. She gradually improved over several months but with residual disability. Physical examination She was afebrile. There was no palpable lymph node or skin rash. She was fully conscious and orientated. There was no neck stiffness. She had left homonymous hemianopia, right partial ptosis, and a small reactive right pupil. Fundoscopic examination was normal. She required a wheel-chair for ambulation. Her left upper limb was flexed at her elbow. Her left arm and leg were weak (power of grade 3/5 to 4/5), with spasticity and hyperreflexia. Her plantar response was upgoing on the left and down-going on

Case 12.4 Neurology 175 the right. Her peripheral sensations were intact, but she had left- sided sensory neglect. She was in sinus rhythm, and examination of her cardiovascular system did not reveal any carotid bruit or heart murmur. Her blood pressure was 130/80 mmHg. Chest and abdominal examinations were normal. Investigations CXR and ultrasound examination of her abdomen and pelvis were normal. Repeated smear and culture of her blood, urine, and wound swab were negative. Her echocardiogram was normal. Shortly after the development of confusion and disorientation, an urgent CT brain had revealed a large hypodense lesion in her right pari- eto-temporal region compatible with a cerebral infarction. CSF examination showed an opening pressure of 34 cm (water), CSF protein 3.79 g/L, CSF glucose 2.1 (serum glucose 6.4), CSF white cell count 30 (lymphocytes 56%, neutrophils 40%, monocyte 4%), RBC 11, and Gram stain negative. One week after lumbar punc- ture, polymerase chain reaction was positive for Mycobacterium tuberculosis DNA in her CSE. Questions 1. What is the most likely cause for her fallopian tube blockage? * Tuberculous salpingitis. 2. Why did she develop persistent fever after delivery of her baby? * Reactivation of tuberculosis with development of tuberculous meningitis. 3. From the CSF examination results, apart from TB menin- gitis, what other diseases could give a similar clinical picture? * Partially treated bacterial meningitis, fungal meningitis. 4. What empirical antibiotic regimen was most likely given initially, and what antibiotic change would occur to cover for listeriosis? * Intravenous high-dose penicillin G and a third-generation cephalosporin; high-dose ampicillin instead of penicillin G.

176 Problem-Based Medical Case Management Case 12.4 5. What is the possible mechanism for developing her cerebral infarction? ¢ Thrombosis secondary to arteritis. 6. What are the other complications of tuberculous meningitis and how are they treated? ¢ Hydrocephalus (shunting), cranial nerve palsies (steroids), tuberculoma (steroids, anti-inflammatory drugs), spinal block (steroids), tuberculous brain abscess (surgical drainage); anti- tuberculous chemotherapy is required in all cases. 7. What anti-tuberculous regimen was most likely started, and how long should she remain on the treatment? ¢ Isoniazid with vitamin B6 (pyridoxine), rifampicin, ethambu- tol, pyrazinamide; for 9 to 12 months. 8. What are the side effects of each of the drugs used in the regimen, and, if appropriate, what precautions would you take to prevent these side effects or minimize their impact on the patient? ¢ Isoniazid: hepatitis (desensitization), peripheral neuropathy (vitamin B6); rifampicin: drug interactions (review drug chart), hepatitis (desensitization), fever and vasculitis (cessation), nausea and vomiting (daily); ethambutol: optic neuritis (regular monitoring by ophthalmologist), hepatitis (desensitization); pyrazinamide: hepatitis (desensitization), gout (colchicine and allopurinol). 9. Why was dexamethasone given with the anti-tuberculous treatment, and under what other circumstances would you add steroids to the treatment? e For anti-inflammatory effects in Medical Research Council Stage II or III disease: lethargy, prominent meningeal irritation, cranial nerve palsies, convulsion, paralysis, stupor, coma. 10. Which of these anti-tuberculous drugs can be safely used in pregnancy with a minimal amount of teratogenicity? * Isoniazid with vitamin B6 (pyridoxine), rifampicin, ethambutol.

g Case 12.4 Neurology 177 Pitfalls and tips + Difficult to differentiate coexisting left homonymous visual field loss (lesion affecting her right optic radiation) and left sensory neglect (lesion affecting her non-dominant right pari- etal lobe) « Failure to associate tuberculous meningitis with stroke * Poor knowledge in management of tuberculous infections