Progressive Multifocal Leukoencephalopathy

Paing P Myint 04386817 MBChB VI

Zodwa Emmah Khumalo GT 63945022 37 year old female

Presenting complaint:
Mrs Khumalo was referred to Steve Biko Academic Hospital on 28 June 2012 from Tshwane District hospital. The patient presented with bilateral blindness for 2 weeks and a left sided hemiparesis and hemiaesthesia for 4 weeks. The working diagnosis was a cerebro-vascular incident and she was sent to SBAH for a comprehensive assessment and further management.

Neurological history:
On admission, the patient was slightly disoriented and a getting the history from her was challenging. She said that a month previously she had sudden weakness of her left arm and leg. The patient did not report any history of trauma. She did not seek medical attention at this time. Two weeks later, she suddenly went blind. This is when she sought medical attention. She did not complain of a headache, dysphagia or sleep disturbances. The weakness had not fluctuated. We were able to obtain a collateral history from her children whom she lives with. According to her eldest child, She began to get sick in March 2012, she complained of feeling weak and dizzy. She was also suffering stress which led to depression as no one in the family was working. She began to forget things and lost her sight in April 2012. She was mentally disturbed. She was unable to concentrate and became very short tempered. Then in June 2012, she had a stroke and was treated at a nearby hospital. Her condition improved but she then had a second stroke after which she was referred to hospital by her sister.

Medical history:
HIV+ (tested on the week of admission at a clinic) No other chronic illnesses. CVI x 2 in the past 2 months No known allergies

Surgical history:
Nil

Family history:
No family history of note.

Social history:
Lives in a house with her sister and her children. She is married and unemployed. She has no medical aid and her highest level of education is grade two. She does not smoke nor does she drink alcohol. No history of substance abuse.

Medications:
Nil
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General examination:
Patient was not acutely ill. Vitals stable on admission GCS 14/15: Eye movements 4/4, Verbal responses 4/5, Motor component 6/6. She was able to speak and respond to questions but she was disorientated at times. She had no signs of chronic disease. No jaundice, anaemia, clubbing, cyanosis, oedema or lymphadenopathy.

Systemic examination:
Cardiovascular system: On inspection, no visible abnormalities or scars of the chest. No visible pulsations. On palpation, no abnormal heaves or murmurs palpable. Apex in 5th intercoastal space in the left mid clavicular line. On percussion, no cardiomegaly, normal percussion notes. On auscultation, S1 and S2 audible. No additional sounds or murmurs. Pulses were present, regular in rate, rhythm and volume. No evidence of peripheral vascular disease. No carotid bruits. Respiratory system: On inspection, no visible abnormalities or scars of the chest. Equal lung expansion bilaterally. No cyanosis. Trachea in the midline. On palpation, equal lung expansion bilaterally. Vocal fremitus normal. On percussion, normal percussion notes over the front and back of the chest On auscultation, good airway entry bilaterally. No crepitations, wheezes or crackles audible over the front and back of the chest. Abdominal exam: On inspection, no visible deformities or scars of the abdomen. No visible pulsations. On palpation, soft, non-tender abdomen. No hepatomegaly, no nodules palpable. No splenomegaly. No rebound tenderness or guarding. On percussion, normal percussion notes over the respective areas. No percussion tenderness. No ascites. On auscultation, normal bowel sounds heard over 4 quadrants

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Neurological Examination
Higher Mental Functions: Mayo Mini-Mental State Examination The patients higher mental functions were tested using the Mayo Mini-Mental State Examination out of 38. The patient scored 23 out of 38. 1. Orientation Full Name Address Current location: building, town, province Date: day, month, year 2. Attention span A string of 7 digits 3. New learning 4 objects listed and asked to recall immediately Name Khoza Items Apple and Table Abstract thought Jealousy 4. Calculating ability Addition 27 + 32 Subtraction 45 8 Multiplication 7 x 9 Division 69/3 5. Abstract similarities Dog and cat Apple and banana Table and chair 6. Constructional ability Three-dimensional figure A clock at 11:15 7. General knowledge Current President Past President What is an island? How many weeks in a year? 7/8

3/7

3/4

2/4

3/3

0/4

3/4

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8. Ability to recall Recall the 4 previously learnt objects

2/4

Total: 23/38 However the patient only had schooling up to grade two, which explains the difficulty with calculations. Furthermore, her constructional ability could not be tested as she was blind. Mrs Khumalo was confused at the time of the initial MMSE and she lost points with regards to orientation and some general knowledge. The patient had been transferred to SBAH and could well not have been informed about her current location, thus would lose points here. Neck Stiffness Brudzinski Test: The patient was asked to lay supine. The neck was passively flexed. There was no stiffness or pain when the neck was flexed, and there was no reflex flexion of the hip. Kernig Test: The patient was asked to lay supine. The patients hip was flexed and the knee was extended. The patient reported no pain in her lower back and hamstrings, and there was no reflex flexion of the other hip. Cranial Nerves CN I Olfactory nerve The patient was able to identify a specific smell in each nostril, with one nostril tested at a time whilst the other was closed with a finger with the eyes closed. Coffee and fruit juice were used in the test. The Olfactory nerve is therefore intact. CN II Optic nerve The patient was blind. Visual acuity. Had the patient been able to see I would have tested it by asking the patient to stand 6m away with one eye closed, the patient is asked to read the letters out aloud. In order to achieve a certain VA, the patient must have 50% or more of that line correct. Visual fields Had the patient been able to see, I would have stood a metre from the patient and asked her to look straight at my nose. With her left eye closed and my right eye closed, I would put up different number of fingers in each quadrant. This would be repeated for the other eye. Pupillary light reflexes A mini-flash light was used to assess the patients pupillary reflexes. The direct reflex was tested by shining the light into one eye and constriction of the pupil noted. This was repeated for the other eye, which also constricted appropriately. The indirect reflex was assessed by shining the light into one eye and noting the pupillary constriction in the other eye. The same was done on the contralateral side. The direct and indirect light reflexes were intact in both eyes. This meant that her Optic nerve (afferent limb of the papillary reflex) was intact.

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Accommodation Had the patient been able to see I would have asked the patient to focus on my finger at about 1 metre away, and then quickly move my finger about 10 cm away from her face noting any pupillary constriction in both eyes. Fundoscopy was attempted in both eyes. An opthalmoscope was used, set at first on positive 10, to identify her red reflex. Once identified, it was moved closer to her and readjusted to accommodate for my eye sight. A vessel was identified and followed to the optic disc. Her red reflex was present, the vessels appeared normal. No signs of papilloedema, optic disc atrophy, retinal exudates or haemorrhages were visible. The patient was bilaterally blind with intact pupillary reflexes bilaterally. This indicates that the lesion could be at cortical level i.e. cortical blindness. CN III, IV, VI Oculomotor, Trochlear and Abducens Nerves The patient did not have ptosis of either eye, and the pupils were equally reactive to light as noticed upon examination of the Optic nerve. Had the patient been able to see, I would have asked the patient to follow my finger while keeping her head fixed. I would have moved my finger in an H-formation and assessed her eye movements as well as looking for any nystagmus. With the patient being blind, I was unable to conduct a typical examination of the eye movements. At best I was able to ask her to try and follow my voice while keeping her head fixed. The patient was able to move her eyes in all 6 directions. The patient was able to depress, elevate and adduct both eyes, thus the Oculomotor nerves were intact as they innervate the medial, superior and inferior rectus muscles responsible for the above mentioned movements. The patient was also able to adduct and depress both eyes meaning that the Trochlear nerves were intact. The patient was also able to abduct both eyes, meaning that the Abducens nerves were intact Pupillary constriction was observed in both eyes when the Optic nerve was tested. This also means that the efferent limb of the papillary reflex supplied by Oculomotor nerve is intact. CN V Trigeminal nerve The patient was inspected for visible obvious wasting of the temporalis and masseter muscles. No visible wasting was present. Sensory: Light touch and Pain, were tested by gently stroking a piece of cotton wool (light touch), followed by light pin pricks (pain) in the three divisions V1 (ophthalmic), V2 (maxillary) and V3 (mandibular) branches. The patient was asked to close her eyes and to comment if she felt the stimuli and if there was a difference in feeling on both sides of the face. Her sensation was intact and equal on both sides. Motor: The patient was asked to bite down, while the temporalis muscle was palpated to test the power of the muscle. The patient was asked to relax and then asked to bite down again while palpating the masseter muscle. Both muscles had normal power (5). The patients lips were separated, and she was asked to open her mouth, observing for any deviation of the jaw. No deviation was visible. The patient was asked to open her mouth against resistance to test the power of her pterygoids which were also (5).
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Reflexes: To test the corneal reflex, cotton wool rolled into a wisp is used. The patient was asked to focus on my assistants voice as she was blind. The cotton wool was brought across the patients sclera from the contralateral side. Both eyes blinked, meaning the corneal reflex was positive. The test was repeated in the other eye with a positive corneal reflex. The jaw jerk was tested by placing the thumb over the patient's chin with the mouth slightly open, and dropping the reflex hammer onto the thumb. There was no obvious brisk jaw jerk reflex. CN VII Facial nerve On inspection of the face, slight asymmetry of the left half of her face was observed. The patient also had visible drooling from the left side of her face. The patient was asked to smile and there was clear left sided weakness of the Facial nerve. There was no visible atrophy. Motor: The patient was asked to frown to test her Frontalis muscle on both sides of her face. No asymmetry was noted, the power was assessed by attempting to force open the creases on the forehead. The creases could not be opened on both sides. Next the patient was asked to close her eyes as tightly as possible and not to let me pry them open to test the power of the Orbicularis oculi. The eyelids on the left side of the face were easily opened while the eyelids on the right were not. Next the patient was asked to close her lips as tightly as possible and not to let me separate the lips at the corners of the mouth to test the Orbicularis oris. Again, the lips on the left were easily separated, but the lips on the right were not. Then the patient was asked to blow up her cheeks on both sides, and to keep her lips closed, not to let air out upon pressure of the cheeks. Air did not escape on the tight but it did escape on the left. Finally the patient was asked to make a grimace to test the power of the Platysma. Again, the left side was weaker than on the right. This was in keeping with an Upper Motor Neuron lesion of the Facial nerve. Taste: The patient was asked to taste a sample of sugar on the anterior of the tongue, and this was intact. Posterior auricular sensation: The patient was asked if she could feel stimulus behind her ears and to comment on any difference between the two sides. The sensation was equal on both sides. CN VIII Vestibulocochlear nerve Cochlear division Whisper test: The patients one ear was closed with my hand and whispered a number to her other ear. She was able to repeat the number. The same was done on the contralateral ear using another number, and she was able to repeat the new number. Rinne test: A 256Hz tuning fork was used for the Rinne test. The tuning fork was struck and placed on patients mastoid process. The patient was instructed to tell me when she could no longer hear it, upon which the tuning fork was moved in front of the external meatus, and asked her if she could hear it then. This was repeated on the contralateral side. On both occasions, her air conduction was better than bone conduction.

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Weber test: A 256Hz tuning fork was used for the Weber test. The vibrating tuning fork was placed in the midline of his forehead, and was asked where she heard the sound coming from. The sound lateralised equally to both sides. The cochlear division of the Vestibulocochlear nerve was intact. Vestibular division No nystagmus was observed. CN IX, X Glossopharyngeal and Vagus nerves On inspection of the palate, no visible abnormalities were detected. Both arches were equal and the uvula was central. No swallowing difficulties were experienced as the patient had been eating with no difficulty before the examination. The soft palate was touched with a wooden spatula and her gag reflex was present. Sensation of both faucical pillars was intact. Taste of the posterior 1/3 of the tongue was also intact. CN XI Accessory nerve No obvious atrophy or asymmetry was observed in the trapezius and sternocleidomastoid muscles. The patient was asked to turn her head to the sides against resistance to test the sternocleidomastoids, as well as to shrug her shoulders against resistance to test the trapezius. She was able to do both of these with the power being (5). CN XII Hypoglossal nerve The patient was asked to open her mouth and to keep her tongue in resting position. No fasciculations or atrophy was identified. The patient was asked her to stick out her tongue to look for any deviation, which there was none. The patient was able to move her tongue from side to side at a quick pace. The patient was asked to push her tongue against the inside of her cheek against resistance. The power was (5). Summary of cranial nerves: CN II: Bilaterally blind, unable to test visual acuity and visual fields. Pupillary reflexes intact. Fundoscopy normal. Possible cortical blindness CN VII: Visible asymmetry and drooling from the left side of the mouth. Right sided UMN lesion due to upper left half of the face being spared, with weakness of the left lower half of the face.

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Motor System The power was tested by asking the patient to move their limbs individually, and to oppose the resistance applied to the limb. This was then graded out of 5, with 5 being normal power, and 0 being no movement. Specific muscles are tested by specific movements.

Movement around joint

Muscle

Segmental Supply

Peripheral Nerve

Power Left Right

Shoulder Abduction Adduction Deltoid Pectoralis anterior Latissimusdorsi Elbow Flexion Extension Thumb- nose Wrist Flexion Flexor carpi radialis Flexor carpi ulnaris Extension Extensor carpi radialis longus Extensor carpi ulnaris Supination Pronation Fingers MCP joint: Flexion Extension PIP joint: Flexion Lumbricalis Extensor digitorum Flexor digitorumsuperficialis C8, T1 C7, C8 C8 Median (I+II), Ulnar (III+IV) Radial nerve Median nerve 0 0 0 5 5 5 Supinator Pronator Teres C6, C7 C6, C7 Radial nerve Median nerve 0 0 5 5 C6, C7 C8, T1 C6, C7 C7, C8 Median nerve Ulnar nerve Radial nerve Radial nerve 0 0 0 0 5 5 5 5 Biceps Triceps Brachioradialis C5, C6 C7 C6 Musculocutaneous nerve Radial nerve Radial nerve 0 0 0 5 5 5 C5 C5, C6, C7, C8 C5, C6, C7, C8 Axillary nerve Pectoral nerve Pectoral nerve 0 0 0 5 5 5

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DIP joint: Flexion Fingers: Abduction Adduction Little finger abduction Thumb IP joint: Flexion MCP joint: Flexion Extension Abduction Adduction Opponation Hip Flexion Extension Abduction

Flexor digitorumprofundus

C8

Median (I+II), Ulnar (III+IV)

Interossei 1 dorsal interosseus Abductor digitiminimi

s

C8, T1 C8, T1 C8, T1

Ulnar nerve Ulnar nerve Ulnar nerve

0 0 0

5 5 5

Flexor Pollicis Longus

C8, T1

Median nerve

Flexor pollicis brevis Extensor Pollicis Longus Abductor pollicis brevis Adductor pollicis Opponens pollicis

C8, T1 C7, C8 T1 C8, T1 C8, T1

Median nerve Radial nerve Median nerve Ulnar nerve Median nerve

0 0 0 0 0

5 5 5 5 5

Iliopsoas Gluteus maximus Gluteus medius Gluteus minimus

L1, L2, L3 L5, S1, S2 L4, L5, S1

Femoral nerve Inferior gluteus nerve Superior gluteus nerve

0 0 0

5 5 5

Adduction

Adductor longus Adductor magnus

L2, L3, L4 L4, L5

Obturator nerve Sciatic and obturator nerve

Knee Flexion Biceps femoris Semi-membranosus Extension Ankle Dorsiflexion Tibialis anterior L4, L5 Deep peroneal nerve 0 5 Quadriceps femoris L2, L3, L4 Femoral nerve 0 5 L5, S1, S2 Sciatic nerve 0 5

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Plantar flexion

Gastrocnemius Soleus

S1

Tibial nerve

Eversion Inversion Toes Dorsiflexion (toes) Dorsiflexion (big toe) Plantar flexion

Peroneus longus,brevis Tibialis posterior

L5, S1 L4, L5

Superficial peroneal nerve Tibial nerve

0 0

5 5

Extensor digitorumlongus Extensor hallucislongus

L4, L5

Peronealprofundus nerve

L5

Peronealprofundus nerve

Flexor digitorumlongus

S1, S2

Tibial nerve

This clearly showed that the patient had a left sided hemiparesis, with normal power of the right side. Tone was tested by passively moving the different joints of the upper and lower limbs through the full range of movement with the limb at rest, and comparing the resistance felt with different velocities. Left and right sides are also compared.

Tone Upper limb Elbow Forearm Wrist Right N N N Left spastic spastic spastic Lower limb Hip Knee Ankle Right N N N Left spastic spastic spastic

The patient had increased tone, with spasticity being prominent on the left side the body affecting both upper and lower limbs. The right side, both upper and lower limbs, had a normal tone. The patient did not have clonus.
Reflexes Upper limb Biceps C5, C6 Triceps C7 Brachioradialis C6 Right ++ ++ ++ Left +++ +++ +++ Lower limb Patellar L2, L3, L4 Ankle S1, S2 Babinski Right ++ ++ Left +++ +++ -

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The patient had brisk reflexes on the left side of the body in both upper and lower limbs. The right side of the body had normal reflexes in both the upper and the lower limbs. Looking at the examination of the motor system of the patient we can see that: Power: 5/5 on the right upper and lower limbs, 0/5 on the left upper and lower limbs Tone: Normal tone on the right upper and lower limbs, increased tone (spastic) on the left upper and lower limbs. No clonus bilaterally. Reflexes: Normal reflexes on the right upper and lower limbs, with brisk +++ reflexes on the left upper and lower limbs. No babinski responses bilaterally.

This shows signs of an UMN lesion. Sensory System The spinothalamic tracts (pain, temperature) and the dorsal columns (light touch, proprioception and vibration) are mainly responsible for the sensory capabilities. Sensation is then tested in each of the dermatomes, while comparing the left to the right. The patient is asked to comment on the quality of the sensation felt as a percentage compared to a normal area i.e. if a normal areas sensation is 100% then how much is this specific area. Cortical sensation is also tested. The spinothalamic tracts were assessed by evaluating the patient's perception of pain and temperature. The pain fibres are tested by using a pin to prick the patient and the temperature fibres were tested with a cold metal tuning fork. The pin prick and cold object is applied to all the dermatomes and the perception on the left and right sides is compared with the use of percentages to compare to the norm. The patient had fallout of her spinothalamic tracts of the left half of the body across all dermatomes, with intact spinothalamic tracts of the right half of the body across all dermatomes. The dorsal column tracts were assessed by using a piece of cotton wool in each of the different dermatomes to assess the patient's perception of light touch. Left and right sides were again compared to one another. The patient had normal light touch sensation in the right half of the body, with a loss of light touch sensation in the left half of all the dermatomes. Vibration sense was tested using a vibrating tuning fork held on the bony eminences. The patient was able to feel the vibration on the bony 1st meta-tarsal phalangeal joint on the right side, but was only able to feel it at the mastoid process on the left side. Proprioception was assessed by moving joints around their axis by a few millimetres while the patient keeps their eyes closed. The patient must then comment on the direction of movement of the joint. The patient had intact proprioception on the right side of the body but there was a fallout on the left . Each of the following dermatomes were tested: C2 C3 C4 C5 C6 C7 Occiput Circumference of the neck Superior, anterior and posterior shoulder Lateral upper arm Lateral forearm and two lateral fingers Middle finger
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C8 Medial two fingers, medial hand and distal forearm T1 Medial forearm and elbow T2 Medial upper arm T3 Axilla T8 Skin at lower ribs and xiphisternum T10 Skin at navel T12 Skin at pubis L2, L3 Anterior aspect of upper leg and knee L4 Medial lower leg L5 lateral lower leg, dorsum of the foot, big toe S1 Little toe, lateral foot, heel, posterior lower leg S2 Posterior part of upper leg S3,S4, S5 Posterior part of the anus Cortical sensation testing (two-point discrimination, touch localisation, sterognosis, digit writing, sensory extinction and identification of textures) was not carried out as the patient was disorientated and the patient had a hemisensory fallout.

Upper limb Right Light touch (cotton wool) Pain (pin prick) Temperature (ice cube) Vibration (tuning fork) Proprioception Normal Normal Normal Normal Normal Left 0 0 0 0 0 Right Normal Normal Normal Normal Normal

Lower limb Left 0 0 0 0 0

From the sensory examination, we can see that the patient has a left sided hemiaesthesia. Sensation of both the dorsal columns and spinothalamic tracts have been affected. On the right, sensation of both the dorsal columns and spinothalamic tracts are intact.

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Coordination and gait: Cerebellar system Due to the fact that the patient was blind, it was very difficult to test certain aspects of the patients coordination and gait. During the examination, certain signs of cerebelllar dysfunction were not present: no vertigo on history, no nystagmus seen, no hypotonia and no titubation. Speech The patient was asked to repeat the following: Pe Pe Pe (lips) Te Te Te (tongue) Ke Ke Ke (palate) PeTeKe PeTeKe PeTeKe The patient was able to repeat all of the above. Upper Limb Finger-nose test: unable to perform due to blindness Finger-circle test: unable to perform due to blindness Alternating finger (Morschens test) and hand movements: patient was able to perform these movements with her right hand and fingers, but was unable to with her left. Rebound: no rebound with the right arm. Unable to perform with the left Oscillation: no oscillations with the right arm. Unable to perform with the left Line drawing: unable to perform due to blindness Lower Limb Toe-finger test: unable to perform due to blindness Heel-knee-ankle: unable to perform due to blindness Tapping feet: able to perform tapping movements with a regular rhythm with the right foot. Unable to perform with the left Oscillation: no oscillations with the right leg. Unable to perform with the left Gait The patient was disorientated throughout our stay during the rotation. Asking the patient to try and stand was unsuccessful. The patient had a left sided hemiparesis and was blind. If possible, we would have liked to test the following: Normal walking Toe walking Heel walking Tandem walking Romberg test Jumping on one leg Balancing on one leg The patient did not seem to have any signs of cerebellar dysfunction seen on this examination. It would be ideal if the gait examination could have also been performed.

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Assessment 37 year old female, HIV+ not on treatment, CD4 unknown, who presented with a history of left sided hemiparesis and hemianesthesia for 4 weeks and bilateral blindness for 2 weeks. There is a collateral history of 2 x CVI in the past 2 months. On examination, patient was disorientated. Clear signs of an UMN lesion were present, possibly due to the multiple CVIs (left sided hemiparesis with spasticity and brisk reflexes of the left upper and lower limbs). Differential diagnosis Cerebrovascular incident Progressive Multifocal Leukoencephalopathy Acute Disseminated EncephaloMyelitis HIV encephalopathy Brain Tumour Primary CNS Lymphoma

Special investigations Bloods: The following tests were done on admission: FBC, UKE, CMP, random Glucose, ESR, s-Folate, s-Vit B12, RPR and TPHA, ANA, Toxoplasmosis , HIV viral load , CD4 count The results of these and further tests are tabulated below:

28/06/12 Hb MCV MCHC WCC Plt Na+ ClK+ Urea Creatinine Ca2+ Mg2+ PO4CRP HIV CD4 RPR TPHA Vitamin B12
12.4 87.5 31.1 7.44 260 138 103 3.3 1.7 96 2.28 0.83 1.07 Positive 328 Negative Negative >16
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03/07/12
11.7 86.5 31.4 5.62 259 139 102 3.5 2.7 48 2.33 0.97 1.31 29.5

10/07/12
12.7 88.4 31.4 6.65 354 134 101 4.3 3.8 64

8.8

CT (27/06/12): The CT showed hypodense white matter changes in the parietal and occipital lobes, along the optic radiation. The lesions were in the periventricular white matter. The grey matter, basal ganglia, cerebellum and brainstem were all spared. There was no mass effect. The differential given after the CT scan was: HIV encephalopathy, PML, Acute disseminated encephalopathy, CMV associated CNS disease, herpes encephalitis and CNS lymphoma. Lumbar Puncture and CSF analysis (29/06/12): No bacterial antigens Protein 0.57 Glucose 3.7 PMN 4 Lymph 14 Erythrocytes 1030 ADA 5.0 Gram stain Neg RPR Neg TPHA Neg JCV 1.23 x 106 MRI (29/06/12): An MRI was done on 29 June 2012. The results of the MRI are as follows: bilateral, asymmetric mainly white matter abnormalities. The lesions are high signal, affecting mainly the occipital lobes and the edges had restricted diffusion. The following were the differentials offered by the radiologist: PML, Acute disseminated encephalomyelitis and PRESS. The special investigations done above were in keeping with progressive multifocal leukoencephalopathy, in a known HIV+ patient. The patient had clinical signs in keeping with PML, MRI findings showing characteristic lesions of PML, and the JC virus was positive in CSF with a high viral load of 1.23 x 106. Thus the diagnosis of PML was made. EEG (03/07/12 and 10/07/12): Commented on in the ward progress section below.

Management:
Clexane 40mg subcutaneous dly Occupational and Physiotherapy: The patient was assessed as completely dependant with regards to bed mobility, dressing, toileting, standing, eating and drinking, washing, sitting and walking. She was dependant for transfer into and out of a wheelchair. She was also not orientated and had poor motivation, poor short term memory and poor level of arousal. The patient required maximal assistance in rolling and sitting; she had associated reactions in her left upper limb. Her left elbow showed hypertonicity and there was weakness in her shoulder, wrist and hand. With regards to sensation, she had a loss of proprioception. The plan was to try increase her upper limb function and to increase her activities of daily living. By 9 July 2012 she was able to maintain a sitting position for 20 seconds. She showed some
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improvement but mostly she needed maximal assistance. Her level of arousal was always poor and she showed difficulty in following basic commands. Social Worker Infectious diseases consult: the patient was seen by the infectious diseases department. They advised us that PML was unlikely in a patient with a CD4 count of 328, and would be more expected when the CD4 was less than 100. However the patient had a CD4 of less than 350, thus qualifying for HARRT: Tenofovir 300mg po nocte, Lamivudine 300mg po nocte and Efavirenz 600 mg po nocte. This was initiated on 09/07/12. Adverse reactions were monitored for, but the patient had none.

Ward progress
The patients level of orientation fluctuated during her stay in the ward. The patient required daily reorientation of date, current location and the reason why she was in the ward. On the night of 02/07/12 the patient had an episode of a generalised tonic-clonic seizure. The patient was given stat dose of Lorazepam and Sodium Valproate by the attending doctor. An EEG was requested the next day which showed marked diffuse encephalopathy which is must more pronounced on the right than the left without epileptiform features. A second EEG was done on 10 July 2012. Once again it was a diffusely abnormal EEG, which was more pronounced on the right. This EEG showed less slowing than the previous EEG. There were no epileptiform features and no findings suggestive of subtle or subclinical seizures. Other than a slight improvement in the sensation of her left arm (the patient experienced pain sensation only in the whole left upper limb), there was no real change in the patients condition while we rotated through the neurology department. Future management for the patient would include continued rehabilitation and HAART. The patients prognosis does not look good; however we can never estimate how long a patient has to live.

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Literature Review: Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is caused by the JC human polyomavirus .(1) It is a disease of the brain that is caused by lytic infection of glial cells in severely immunosuppressed patients and is often fatal. PML is a demyelinating disease of the central nervous system that can occur in patients with severe immunosuppression. In this literature review, I will be discussing Classical PML as a disease process, including the epidemiology, pathogenesis, clinical features, special investigations and advances in the management of PML. Epidemiology PML was regarded as a rare disease before the HIV/AIDS epidemic, and was seen in certain patients that were immunosuppressed i.e. patients with haematological malignancies, organ transplant recipients, and chronic automimmune diseases. Prevelance was estimated to be around 4.4 cases per 100000 of the population. (2) During the HIV/AIDS epidemic, the prevalence increased, where up to 5% of patients with AIDS developed PML. The Swiss HIV cohort study prospectively analyzed the incidence and outcome of PML in 226 cases from 1988 to 2007 (2). The incidence of PML decreased from 0.24 cases/100 PY before 1996 (before HAART) to 0.06 cases/100 PY from 1996 onward. In this study, the PMLattributable 1-year mortality rate was found to decrease from 82.3 cases/100 PY during the pre-HAART era to 37.6 cases/100 PY during the HAART era (2). Certain classes of drugs, such as the immunomodulatory drugs used for autoimmune diseases e.g. Natalizumab and Rituximab, have been associated with PML. (1) Pathogenesis The JC virus is a circular enclosed double-stranded DNA neurotropic virus that infects only human beings.(1) Thus research on the pathogenesis of JC virus has been limited due to the lack of an animal model. The JC virus has been shown to act on a N-linked glycoprotein with an -(2,6)-linked sialic acid receptor and serotoninergic 5-HT2a receptor to infect astroglial cells in culture.(1) These receptors have been show to exist in several different human tissues it is difficult to proliferate the JC virus in human cell cultures.(1) A demyelination of predominantly the white matter in the central nervous system is seen. In certain studies, it has been shown that the JC virus can be detected by PCR in the urine of a third of healthy individuals or immunosuppressed patients with or without PML.(3) However, the JC virus is not usually found in the blood of immunocompetent individuals.(3) The humoral immune response against the JC virus has been extensively studied. The first test to approximately calculate the seroprevalence was the haemagglutination inhibition assay, which dates back to the 1970s. This test was based on the ability of the JC virus to agglutinate human type O erythrocytes in vitro. The presence of antibodies in the serum was indicated by the ability to prevent this agglutination. Using whole JC virions, this test detected a seroprevalence of 60% in individuals aged 2029 years in the USA.(1) More recently, by use of a haemagglutination inhibition assay based on virus-like particles containing the JC virus VP1 major capsid proteins, reported a seroprevalence of up to 50% in individuals aged 6069 years in England and Wales.(1) Many other studies that have been

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done across the globe have shown that different investigations such as quantitative enzyme showed higher titres of JC virus than enzyme immunoassay. (1) These studies have also shown that because a primary infection is not accompanied by a characteristic clinical event, a clearly defined JC virus seronegative population is absent.(1) It has also been shown that increased JC virus specific antibody titres in HIV+ and HIV- patients does not prevent the occurence of PML in patients. The JC virus specific antibodies produced by the host humoral immune response alone are not sufficient to prevent reactivation of the JC virus thus leading to PML. The cellular immune response is necessary for prevention of viral reactivation and proliferation. This response may be mediated by JC virus-specific CD4+ T cells, which have been detected in the blood of patients who have survived PML. (1) It has also been found that CD8+ T cells are the major inflammatory cells found in PML lesions, where they aggregate around infected cells.(1)

(4)
Life cycle of JCVand therapeutic targets. The steps in the life cycle of JCVare indicated by numbers in black as follow: 1adsorption of virus to cell surface receptors; 2entry by clathrin-dependent endocytosis; 3 transport to the nucleus; 4uncoating; 5transcription of the early coding region; 6translation of early mRNAs to produce the early regulatory proteins, large Tantigen, small t antigen, and the alternatively spliced T antigens: T135, T136, and T165; 7nuclear localization of large Tantigen; 8replication of viral genomes; 9transcription of the viral late genes; 10translation of viral late transcript to produce agnoprotein and the capsid proteins (VP1, VP2, and VP3); 11nuclear localization of capsids; 12assembly of viral progeny in the nucleus; 13release of virions by an unknownmechanism; 14released virions. Targets for drug intervention are indicated by letters in red as follows: Avirus/receptor interaction; Bviral entry; Cviral replication; D viral transcription (4)

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Diagnostic Criteria(4) Definitive (causative) diagnosis: PML is confirmed by histopathology (tissueconfirmed PML) where there is evidence of consistent neuropathology of the brain as seen on biopsy or autopsy and JC Virus DNA/protein detected. Laboratory-confirmed (probable) diagnosis: Polymerase chain reaction assays of JC Virus from CSF, which has a lower sensitivity and specificity even amongst different laboratories Possible diagnosis: clinical and MRI findings consistent with PML without a brain biopsy and lumbar puncture performed OR JC Virus DNA not detected in the CSF.

Clinical Features Typically, PML is caused by the infection of oligodendrocytes and, to a lesser extent, astrocytes. Therefore, neurological deficits that are present in a patient are related to the areas of demyelination in the brain.(1) The presenting symptoms can vary. The most frequent clinical presentation is characterized by motor deficits including muscle weakness, sensory deficits, cognitive dysfunction, gait ataxia, and visual symptoms such as hemianopsia (4). Some studies also reported epileptic seizures occurring in some patients with PML. Epilepsy is usually related to the presence of lesions adjacent to the cortex and does not affect survival (4). Atypical presentations include pure cerebellar syndrome, meningitis, meningoencephalitis, progressive myoclonic ataxia and muscle wasting associated to extrapyramidal signs (4). The JC virus has also been reported in neuroncology, such as gioblastomas, astrocytomas olygodendrogliomas, and gastrointestinal cancers, and an extensive review of this was recently published (4). The disease does not usually involve the optic nerves or the spinal cord, however incidental spinal cord demyelination has been reported in an autopsy study (1). Laboratory Findings Polymerase chain reaction of JC virus DNA in CSF before the introduction of HAART had a sensitivity of 72-92% and a specificity of 92-100%. Once HAART had been introduced, the specificity had dropped to 58% most likely due to improved immune control of the JC virus and the CSF clearance of the virus by immune cells (4). This means that false negative PCRs can occur. Radiological findings On MRI and CT imaging, brain lesions can be seen in the white matter, which do not correlate to specific vascular territories. On CT, these lesions appear as hypodense or patchy areas. On MRI areas of hyperintensity on T2-weighted and fluid attenuated inversion recovery images, and hypointensity on T1-weighted images. (1) Patients usually have multiple lesions frequently in the subcortical hemispheric white matter or the cerebellar peduncles. PML lesions can also be seen in grey matter structures such as the basal ganglia
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or the thalamus where myelinated fibres may be located. Classical PML lesions do not show signs of oedema, contrast enhancement or mass effect on imaging.(4)

Magnetic resonance imaging of a case of progressive multifocal leukoencephalopathy. What is shown in the image is an axial T2-weighted sequence showing multiple hyperintense lesions involving both the superficial and the deep white and the gray matter (arrows) (4)

Treatment There is no specific antiviral drug against the JC virus. Cidofovir (an antiviral used in CMV infections) was studied retrospectively as it initially showed promise in improving survival of HIV+ patients with PML when used in combination with HAART. However a multicohort analysis of the efficacy of Cidofovir treatment of HIV+ patients with PML, combined data from one prospective study and five cohort studies that also assessed patients who were already on HAART. No survival benefit was seen for patients who received cidofovir and it did not improve PML-related residual disability by 12 months. (5) Cytarabine, a chemotherapeutic drug that inhibits JC virus replication in vitro also showed some promise in certain studies where it was associated with stabilisation of PML in HIVpatients with another form of immunosuppressive disorder such as leukaemia or lymphoma. However in another randomised control study, it was shown that there was no survival benefit when using antiretrovirals were used only against Cytarabine with antiretrovirals. (1) Since the recent discovery of the JC viruss capability to enter cells via 5-HT2A receptors, more attention has been paid to serotonin receptor blockers such as Mirtazapine. In a recent study, the 1-year survival rate was 62% among 14 patients with PML treated with mirtazapine compared with 45% in 11 untreated patients. (1)
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Recently during a screening of drugs, Mefloquine (an antimalarial) was demonstrated to possibly inhibit the JC virus replication in a cell culture system.63 A multicentre worldwide clinical trial is now investigating the use of mefloquine for the treatment of PML.(1) The goals in treating PML is to restore the hosts adaptive immune response to JC virus to control the infection. In HIV+ patients, this is mainly achieved my HAART. Thus, HAART remains the mainstay of treatment of PML in HIV+ patients. In HIV- patients, the main goal is to decrease the use of immunosuppresents. However, in cases such as organ transplant recipients, this may lead to graft rejection. In such patients immunotherapies that increase the cellular immune response to the JC virus may prove to be a better option. In conclusion, PML remains to be a fatal demyelinating disease mainly of the white matter that predominantly affects the immunosuppresed population. Clinical presentations can vary between patients and diagnosis is best confirmed via hisopathology. However, with the introduction of HAART over the past couple of decades, we have seen an improvement in outcome of patients with PML. As stated above HAART remains the mainstay of treatment in HIV+ patients. New therapeutic options such as Mefloquine are being investigated and may have a better outcome for patients which will be seen in the near future. References 1. Tan S, Koralnik I. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurology 2010; 9: 42537 2. Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clinical Infectious Diseases 2009; 48: 14591466. 3. Koralnik IJ, Boden D, Mai VX, et al. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999; 52: 25360. 4. Tavazzi E, White M, Khalili K. Progressive multifocal leukoencephalopathy: clinical and molecular aspects. Reviews in Medical Virology. 2012; 22: 1832 5. De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not eff ective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 2008; 22: 175967.

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