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37 year old female
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
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.”
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
No family history of note.
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.
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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
On inspection, no visible abnormalities or scars of the chest. No visible pulsations.
On palpation, no abnormal heaves or murmurs palpable.Apex in 5thintercoastal 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.
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.
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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Higher Mental Functions: Mayo Mini-Mental State Examination
The patient’s higher mental functions were tested using the Mayo Mini-Mental State
Examination out of 38. The patient scored 23 out of 38.
Current location: building, town, province
Date: day, month, year
2. Attention span 3/7
A string of 7 digits
3. New learning 3/4
4 objects listed and asked to recall immediately
Name – Khoza
Items – Apple and Table
Abstract thought – Jealousy
4. Calculating ability 2/4
Addition – 27 + 32
Subtraction – 45 – 8
Multiplication – 7 x 9
Division – 69/3
5. Abstract similarities 3/3
Dog and cat
Apple and banana
Table and chair
6. Constructional ability 0/4
A clock at 11:15
7. General knowledge 3/4
What is an island?
How many weeks in a year?
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8. Ability to recall 2/4
Recall the 4 previously learnt objects
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.
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
Kernig Test: The patient was asked to lay supine. The patient’s 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.
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 fieldsHad 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
Pupillary light reflexesA mini-flash light was used to assess the patient’s pupillary reflexes.
The direct reflex was tested by shining the light intoone eye and constriction of the pupil
noted. This was repeated for the othereye, 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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AccommodationHad 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 re-
adjusted 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
patient’s 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 wispis used. The patient was
asked to focus on my assistant’s voice as she was blind. The cotton wool was brought across
the patient’s 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
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
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 ⅔ 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
CN VIII – Vestibulocochlear nerve
Whisper test:The patient’s 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 patient’s 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.
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
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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.
Peripheral Nerve Power
Abduction Deltoid C5 Axillary nerve 0 5
Adduction Pectoralis anterior
C5, C6, C7, C8
C5, C6, C7, C8
Flexion Biceps C5, C6 Musculocutaneous nerve 0 5
Extension Triceps C7 Radial nerve 0 5
Thumb- nose Brachioradialis C6 Radial nerve 0 5
Flexion Flexor carpi radialis
Flexor carpi ulnaris
Extension Extensor carpi
Extensor carpi ulnaris
Supination Supinator C6, C7 Radial nerve 0 5
Pronation Pronator Teres C6, C7 Median nerve 0 5
Median (I+II), Ulnar (III+IV)
C8 Median nerve 0 5
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Plantar flexion Gastrocnemius
S1 Tibial nerve 0 5
Eversion Peroneus longus,brevis L5, S1 Superficial peroneal nerve 0 5
Inversion Tibialis posterior L4, L5 Tibial nerve 0 5
L4, L5 Peronealprofundus nerve 0 5
Extensor hallucislongus L5 Peronealprofundus nerve 0 5
Plantar flexion Flexor digitorumlongus S1, S2 Tibial nerve 0 5
This clearly showed that the patient had a left sided hemiparesis, with normal power of the
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.
Upper limb Right Left Lower limb Right Left
Elbow N ↑spastic Hip N ↑spastic
Forearm N ↑spastic Knee N ↑spastic
Wrist N ↑spastic Ankle N ↑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.
Upper limb Right Left Lower limb Right Left
Biceps C5, C6 ++ +++ Patellar L2, L3, L4 ++ +++
Triceps C7 ++ +++ Ankle S1, S2 ++ +++
Brachioradialis C6 ++ +++ Babinski - -
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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.
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 area’s 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 ofthe
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:
C3 Circumference of the neck
C4 Superior, anterior and posterior shoulder
C5 Lateral upper arm
C6 Lateral forearm and two lateral fingers
C7 Middle finger
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C8 Medial two fingers, medial hand and distal forearm
T1 Medial forearm and elbow
T2 Medial upper arm
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 Lower limb
Right Left Right Left
Light touch (cotton wool) Normal 0 Normal 0
Pain (pin prick) Normal 0 Normal 0
Temperature (ice cube) Normal 0 Normal 0
Vibration (tuningfork) Normal 0 Normal 0
Proprioception Normal 0 Normal 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
patient’s coordination and gait. During the examination, certain signs of cerebelllar
dysfunction were not present: no vertigo on history, no nystagmus seen, no hypotonia and
The patient was asked to repeat the following:
The patient was able to repeat all of the above.
Finger-nose test: unable to perform due to blindness
Finger-circle test: unable to perform due to blindness
Alternating finger (Morschen’s 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
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
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:
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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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).
- Cerebrovascular incident
- Progressive Multifocal Leukoencephalopathy
- Acute DisseminatedEncephaloMyelitis
- HIV encephalopathy
- Brain Tumour
- Primary CNS Lymphoma
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 03/07/12 10/07/12
Hb 12.4 11.7 12.7
MCV 87.5 86.5 88.4
MCHC 31.1 31.4 31.4
WCC 7.44 5.62 6.65
Plt 260 259 354
Na+ 138 139 134
Cl- 103 102 101
K+ 3.3 3.5 4.3
Urea 1.7 2.7 3.8
Creatinine 96 48 64
Ca2+ 2.28 2.33
Mg2+ 0.83 0.97
- 1.07 1.31
CRP 29.5 8.8
Vitamin B12 >16
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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
Gram stain Neg
JCV 1.23 x 106
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
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.
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.
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
ponocte, Lamivudine 300mg ponocte and Efavirenz 600 mg ponocte. This was
initiated on 09/07/12. Adverse reactions were monitored for, but the patient had
The patient’s 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
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
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 patient’s
condition while we rotated through the neurology department.
Future management for the patient would include continued rehabilitation and HAART. The
patient’s prognosis does not look good; however we can never estimate how long a patient
has to live.
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Literature Review:ProgressiveMultifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) iscaused by the JC human
polyomavirus.(1)It is a diseaseof the brain that is caused by lytic infection of glial cells
inseverely immunosuppressed patients and is often fatal.PML is a demyelinating disease of
the central nervous system that canoccur 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.
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
HIVcohort study prospectivelyanalyzed the incidence and outcome of PML in226 cases from
1988 to 2007 (2). The incidence ofPML decreased from 0.24 cases/100 PY before
1996 (before HAART) to 0.06 cases/100 PY from 1996onward. In this study, the PML-
attributable 1-yearmortality rate was found to decrease from 82.3 cases/100 PY during the
pre-HAART era to 37.6cases/100 PYduring 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)
The JC virus is a circular enclosed double-stranded DNA neurotropic virus that infects
onlyhuman 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 α-(2,6)-linked sialic acid receptor and serotoninergic 5-HT2a receptor toinfect
astroglial cells in culture.(1) These receptors have been show to exist in several different
human tissuesit is difficult to proliferate the JC virus in human cellcultures.(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 urineof
a third of healthy individuals or immunosuppressedpatients with or without PML.(3)
However, the JC virus isnot usually found in the blood of immunocompetentindividuals.(3)
The humoral immune response against the JC virushas been extensively studied. The first
test to approximately calculate the seroprevalence was the haemagglutination
inhibitionassay, which dates back to the 1970s. This test was based on the abilityof the JC
virus to agglutinate human type O erythrocytesin vitro. The presence of antibodies in the
serum wasindicated by the ability to prevent this agglutination.Using whole JC virions, this
test detected a seroprevalenceof 60% in individuals aged 20–29 years in the USA.(1)More
recently, by use of a haemagglutination inhibitionassay based on virus-like particles
containing the JC virusVP1 major capsid proteins, reported a seroprevalence of up to 50% in
individualsaged 60–69 years in England and Wales.(1)Many other studies that have been
20. Page 20 of 24
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 occurenceof PML in patients. The JC virus specificantibodies produced
by the host humoral immuneresponse alone are not sufficient to prevent reactivationof the
JC virus thus leading to PML. The cellular immuneresponse is necessary for prevention of
viral reactivationand proliferation. This response may be mediated byJC virus-specific CD4+
T cells, which have been detectedin 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)
Life cycle of JCVand therapeutic targets. The steps in the life cycle of JCVare indicated by numbers in black as
follow: 1—adsorptionof virus to cell surface receptors; 2—entry by clathrin-dependent endocytosis; 3—
transport to the nucleus; 4—uncoating; 5—transcription of theearly coding region; 6—translation of early
mRNAs to produce the early regulatory proteins, largeTantigen, small tantigen, and the alternativelyspliced T’
antigens: T’135, T’136, and T’165; 7—nuclear localization of large Tantigen; 8—replication of viral genomes;
9—transcription ofthe viral late genes; 10—translation of viral late transcript to produce agnoprotein and the
capsid proteins (VP1, VP2, and VP3); 11—nuclearlocalization of capsids; 12—assembly of viral progeny in the
nucleus; 13—release of virions by an unknownmechanism; 14—released virions.Targets for drug intervention
are indicated by letters in red as follows:A—virus/receptor interaction;B—viral entry;C—viral replication;D—
21. Page 21 of 24
- Definitive (causative) diagnosis: PML is confirmed by histopathology (tissue-
confirmed 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
- 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.
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 presentationis 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 somepatients
with PML. Epilepsy is usually related to the presence of lesions adjacent to thecortex and
does not affect survival (4).
Atypicalpresentations include pure cerebellar syndrome, meningitis,meningoencephalitis,
progressive myoclonic ataxiaand muscle wasting associated to extrapyramidalsigns (4). The
JC virus has also been reported inneuroncology, such as gioblastomas,
astrocytomasolygodendrogliomas, 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
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
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 MRIareas of hyperintensity on T2-weighted and fluidattenuated 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
22. Page 22 of 24
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
multifocalleukoencephalopathy. 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)
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 studyand five cohort studies that also assessed patients who were
already on HAART. No survival benefit was seen for patients whoreceived 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 HIV-
patients 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
Since the recent discovery of the JC virus’s 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)
23. Page 23 of 24
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 multicentreworldwide
clinical trial is now investigating the use of mefloquine for the treatment of PML.(1)
The goals in treating PML is to restore the host’s 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
thatpredominantly 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.
1. Tan S, Koralnik I.Progressive multifocal leukoencephalopathy and otherdisorders
caused by JC virus: clinical features and pathogenesis. Lancet Neurology2010; 9:
2. Khanna N, Elzi L, Mueller NJ, et al. Incidenceand outcome of progressive
multifocalleukoencephalopathy over 20 years ofthe Swiss HIV Cohort Study. Clinical
Diseases 2009; 48: 1459–1466.
3. Koralnik IJ, Boden D, Mai VX, et al. JC virus DNA load in patients with and without
progressive multifocal leukoencephalopathy. Neurology 1999; 52:253–60.
4. Tavazzi E, White M, Khalili K. Progressive multifocal leukoencephalopathy: clinical
and molecular aspects. Reviews in Medical Virology. 2012; 22: 18–32
5. De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in additionto antiretroviral
treatment is not effective for AIDS-associatedprogressive multifocal
leukoencephalopathy: a multicohort analysis.AIDS 2008; 22:1759–67.
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