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55 Cases in Neurology
Published online by Cambridge University Press

55 Cases in Neurology
Case Histories and Patient Perspectives
Mark McCarron
Ulster University

Shaftesbury Road, Cambridge CB2 8EA, United Kingdom
One Liberty Plaza, 20th Floor, New York, NY 10006, USA
477 Williamstown Road, Port Melbourne, VIC 3207, Australia
314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre, New Delhi – 110025, India
103 Penang Road, #05–06/07, Visioncrest Commercial, Singapore 238467
Cambridge University Press is part of Cambridge University Press & Assessment,

a department of the University of Cambridge.
We share the University’s mission to contribute to society through the pursuit of
education, learning and research at the highest international levels of excellence.
www.cambridge.org
Information on this title: www.cambridge.org/9781009214117
DOI: 10.1017/9781009214131
© Cambridge University Press & Assessment 2023
This publication is in copyright. Subject to statutory exception and to the provisions
of relevant collective licensing agreements, no reproduction of any part may take
place without the written permission of Cambridge University Press & Assessment.
First published 2023
Printed in the United Kingdom by TJ Books Limited, Padstow Cornwall
A catalogue record for this publication is available from the British Library.
ISBN 978-1-009-21411-7 Paperback
Cambridge University Press & Assessment has no responsibility for the persistence
or accuracy of URLs for external or third-party internet websites referred to in this
publication and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Every effort has been made in preparing this book to provide accurate and up-to-date information that
is in accord with accepted standards and practice at the time of publication. Although case histories
are drawn from actual cases, every effort has been made to disguise the identities of the individuals
involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information
contained herein is totally free from error, not least because clinical standards are constantly changing
through research and regulation. The authors, editors, and publishers therefore disclaim all liability for
direct or consequential damages resulting from the use of material contained in this book. Readers are
strongly advised to pay careful attention to information provided by the manufacturer of any drugs or
equipment that they plan to use.

Contents
Preface ix
Acknowledgements x
Section 1 Visual Disturbance Section 2 Headache and

1 Weight Loss Effects on Vision and Pain
Limbs 1
10 Losing Volume 67
(Progressive peripheral and optic
(Postural headache)
neuropathy)
11 Where Is the Pus? 73
2 Adult-Onset Visual Loss 7
(Back pain with fever)
(Rapid blindness on background of
excess alcohol) 12 Recurrent Acute Headaches 79
(Multiple thunderclap headaches on the
3 A BEE of a Syndrome 13
same day)
(Headache, encephalopathy, unilateral
deafness and asymptomatic branch 13 A ‘Never’ Recurring Event 85
retinal artery occlusion) (Thunderclap headache management)
4 Multiple Problems 19 14 Headache and Fever 91
(Unsteadiness, visual and sphincter (Headache, vomiting and impaired
disturbance) consciousness)
5 Chasing Periorbital Nerves 29 15 Brain Infection 97
(Increasing ophthalmoplegia and (Headache, sweating and
proptosis) unilateral contiguously spreading
paraesthesia)
6 High Pressure 37
(New headache and visual disturbances) 16 Headache and Droopy Eye 105
(Headache, miosis and ptosis)
7 Test Characteristic Limitations 43
(Optic neuritis) 17 Facial Somatic Mosaicism 113
(Port wine stain and severe
8 Temporary Visual Failure 53
migraines)
(Bilateral optic neuropathy)
18 An Alarm Clock Headache 121
9 Chasing the Clot 59
(Nocturnal headache)
(Papilloedema and subsequent seizures)

vi Contents
Section 3 Weakness 32 Personality Change 221

(Disinhibition, apathy and lack of
19 Bleeding Brain 125 empathy behavioural changes)
(Deafness and a spastic leg)
33 Evolving and Changing
20 A Battery Issue 131 Neurology 229
(Proximal weakness, ptosis and (Dissociative attacks and gait
ophthalmoplegia) disturbance)
21 Symptoms Took Years to
Develop 137
(Increasing dysphagia) Section 5 Confusion
22 High-Frequency Improvement 141 34 Clouding of Consciousness in
(Fatigue and erectile dysfunction) Hospital 237
(Limb weakness with subsequent
23 Singling Out Dermatomes 147
encephalopathy)
(Facial weakness with vesicular rash)
35 Leaky Effects of Rising
24 Asthmatic Neurology 155 Pressure 243
(Mononeuritis multiplex) (Encephalopathy and right-sided
25 Neurological Consequences of weakness)
Infection 167 36 Smoking Encephalopathy 249
(Progressive limb weakness) (Cognitive decline)
26 When Speech and Swallow Fail 177 37 Losing Running Memories 255
(Bulbar presentation of slurred speech (Intermittent confusion)
and swallowing difficulty)
27 Recurrent Weakness 185
(Recurrent Guillain–Barré-like Section 6 Movement
presentation)
Disturbances
28 Increasing Golfing Handicap 193
(Progressive myelopathy) 38 Involuntary Arm Movement 263
(Hyperkinetic unilateral limb
movement disorder)
Section 4 Behavioural and 39 Salt Control 269
Language Changes (Acquired ataxia)
29 Emotional Consequences 199 40 A Young Man with More Than
(Buckling legs on laughing and Dizziness 275
involuntary sleeping) (New onset headache with dizziness and
vomiting)
30 Covalent Cascade 207
(Progressive unsteadiness and cognitive 41 Late Familial Falling 281
decline) (Slurring of speech and falling)
31 Progressive Silence 215 42 Non-familial Falling 287
(Progressive aphasia) (A student with a balance problem)

Contents vii
43 Shaking Leg 293 50 Following the Eyes 339

(Progressive limb tremor) (Fluctuating coma, dysarthria and
ocular abnormalities)
44 A Viral Opportunity 299
(Cerebellar syndrome after years of 51 Fuming Loss of Consciousness 345
iatrogenic immunosuppression for (Dangerous slurry fumes)
discoid lupus)
52 From Skin to Brain 351
45 More Searching for Causes of (New onset epilepsy)
Progressive Unsteadiness 307
53 Self-Tolerance Failure 359
(Progressive ataxia)
(Epilepsy and dissociative attacks)
54 Not a Minor Problem 365
Section 7 Acute Onset of (Gearstick and walking problem)
Neurological Symptoms 55 Seized 373

(Medical refractory seizures)
46 A Neurological Miscarriage 315
(Stroke, epilepsy and mid-trimester Perspectives 379
miscarriage)
47 Am I Repeating Myself? 321
(Gym-induced temporary amnesia) Index 383
48 A Raspberry Causing Trouble 325
Colour plates can be found between
(Symptomatic location-related
pages 214 and 215
epilepsy)
49 Different Spells 331
(Transient slurred speech and a numb
hand)

Preface
Case reports remain the cornerstone of learning clinical neurology. Although they are less
frequently reported in medical and neurological journals, conferences and neurology depart-
ments continue to employ case reports as a teaching tool, reflecting the daily experience of
neurologists. So why another neurology case report textbook?
Advances in neuroimaging, evolving diagnostic criteria and differential diagnoses, patient
access to neurologists in district general hospitals, increasing evidence-based management of
neurological disorders and better recognition of patient experience and contribution to man-
agement all prompted this collection of case reports aligned with patient perspectives.
While some of the case reports of rare and uncommon neurological disorders have been
presented locally (Altnagelvin Area Hospital) and at a regional neuroscience centre (Royal
Victoria Hospital, Belfast), common presentations are deliberately included to reflect the dai-
ly experience of patients and neurologists. With that in mind, the book is aimed at junior doc-
tors, medical research fellows considering a career in neurology and early neurology trainees.
The 55 case reports are not meant to be a comprehensive neurology collection but rather
a glimpse at current neurology practice, including clinical clues, neuroradiology findings and
test characteristics of diagnostic investigations. The layout of the history, examination and
preliminary investigations allows the reader to think about the potential diagnosis or differ-
ential diagnosis before reading about the neurological condition and what happened to the
patient.
The author is responsible for any errors. Any learning is to the credit of the patient and
reader.
ix
https://doi.org/10.1017/9781009214131.001 Published online by Cambridge University Press

Acknowledgements
55 Cases in Neurology came to print thanks to the generous support, encouragement and
reviews from a wide range of colleagues. I am indebted to Dr Peter Flynn (neuroradiology), Dr
Gavin McCluskey (neurologist), Dr Ferghal McVerry (neurologist) and Dr Peter M cCarron
(epidemiologist and psychiatrist) for their timely and critical reviews.
Other colleagues who made important contributions include Stephen Payne (medical
photographer), Carrie Wade (personal assistant), Dr Ali Benmusa (pathologist), Dr Brian
Herron (neuropathologist) and Rory Durnin (graphic artist). I offer special thanks to the staff
of Cambridge University Press for their guidance through the project and their editorial work.
Finally, and most importantly, I thank the patients and relatives who took the time to
contribute the patient perspectives in order to educate all of us about the experience of living
with a neurological illness.

Section 1 Visual Disturbance
1 Weight Loss Effects on Vision and Limbs

CASE
History
A 46-year-old right-handed housewife presented with progressive visual disturbance and
sensory impairment of her feet and hands. She complained of a six-month history of pro-
gressive painful paraesthesiae and numbness in her hands and feet. She had then developed
increasingly blurred vision for six to seven weeks prior to presentation. She was a non-smoker
and drank a glass of wine once a week.
In her medical history, she had been obese with a weight of 86 kg and body mass index
(BMI) of 32.8 kg/m2. She had had an 18-month history of nausea, vomiting, anorexia and
weight loss. Her weight had dropped by 25 kg (22% of her body weight), and her dress size
had dropped from size 20 to size 10–12. Investigations by a gastroenterologist revealed an
obstructive liver function pattern with raised alkaline phosphatase and gamma glutamyl
transferase. She had a macrocytosis. Serum folate levels were persistently low, between 0.8 and
2 μg/L (normal range >2.2 μg/L) in the eight months prior to a neurology assessment (Figure
1.1). An upper gastrointestinal endoscopy showed only a hiatus hernia. Liver biopsy showed
non-alcoholic steato-hepatitis (NASH). Two months prior to presentation to neurology she
had been prescribed a one-week course of folic acid replacement; folate levels s ubsequently
improved.
Examination
She had angular stomatitis. She had reduced visual acuity to 6/36 bilaterally. Colour vision
tested using Ishihara plates was reduced at 2/14 on the right and 1/14 on the left. There were
bilateral central scotomas and mild temporal disc pallor on funduscopy, all consistent with
a bilateral optic neuropathy. The remaining cranial nerves were intact. Power was 5/5 in all
limbs. There was a sensory neuropathy with reduced fine touch and pinprick sensation in a
stocking distribution to her knees. There was reduced proprioception and vibration sensation
at both great toes. There was no limb ataxia but her tandem walk was mildly unsteady.
Investigations
A nutritional profile showed normal B12, folate, thiamine, vitamin E, beta carotene and zinc
levels. Vitamins A, C and D as well as selenium levels were all deficient (Table 1.1). Other
investigations including anti-neuronal antibodies, autoimmune serology (neuromyelitis
optica IgG aquaporin 4 and myelin oligodendrocyte glycoprotein antibodies) and immuno-
globulin profile were normal.
MRI of brain and spine and cerebrospinal fluid analysis were normal.
Nerve conduction studies demonstrated a severe length-dependent axonal sensory
neuropathy.
Visual evoked responses showed no consistent response from either eye. Somatosensory
evoked potentials and electroretinogram were normal.

Section 1 Visual Disturbance
1 Weight Loss Effects on Vision and Limbs

CASE
History
A 46-year-old right-handed housewife presented with progressive visual disturbance and
sensory impairment of her feet and hands. She complained of a six-month history of pro-
gressive painful paraesthesiae and numbness in her hands and feet. She had then developed
increasingly blurred vision for six to seven weeks prior to presentation. She was a non-smoker
and drank a glass of wine once a week.
In her medical history, she had been obese with a weight of 86 kg and body mass index
(BMI) of 32.8 kg/m2. She had had an 18-month history of nausea, vomiting, anorexia and
weight loss. Her weight had dropped by 25 kg (22% of her body weight), and her dress size
had dropped from size 20 to size 10–12. Investigations by a gastroenterologist revealed an
obstructive liver function pattern with raised alkaline phosphatase and gamma glutamyl
transferase. She had a macrocytosis. Serum folate levels were persistently low, between 0.8 and
2 μg/L (normal range >2.2 μg/L) in the eight months prior to a neurology assessment (Figure
1.1). An upper gastrointestinal endoscopy showed only a hiatus hernia. Liver biopsy showed
non-alcoholic steato-hepatitis (NASH). Two months prior to presentation to neurology she
had been prescribed a one-week course of folic acid replacement; folate levels s ubsequently
improved.
Examination
She had angular stomatitis. She had reduced visual acuity to 6/36 bilaterally. Colour vision
tested using Ishihara plates was reduced at 2/14 on the right and 1/14 on the left. There were
bilateral central scotomas and mild temporal disc pallor on funduscopy, all consistent with
a bilateral optic neuropathy. The remaining cranial nerves were intact. Power was 5/5 in all
limbs. There was a sensory neuropathy with reduced fine touch and pinprick sensation in a
stocking distribution to her knees. There was reduced proprioception and vibration sensation
at both great toes. There was no limb ataxia but her tandem walk was mildly unsteady.
Investigations
A nutritional profile showed normal B12, folate, thiamine, vitamin E, beta carotene and zinc
levels. Vitamins A, C and D as well as selenium levels were all deficient (Table 1.1). Other
investigations including anti-neuronal antibodies, autoimmune serology (neuromyelitis
optica IgG aquaporin 4 and myelin oligodendrocyte glycoprotein antibodies) and immuno-
globulin profile were normal.
MRI of brain and spine and cerebrospinal fluid analysis were normal.
Nerve conduction studies demonstrated a severe length-dependent axonal sensory
neuropathy.
Visual evoked responses showed no consistent response from either eye. Somatosensory
evoked potentials and electroretinogram were normal.

2 Visual Disturbance
Table 1.1 Micronutrient levels at baseline, 12 and 84 months
Vitamin or mineral Baseline values 12 months 84 months Normal ranges

B12 (ng/L) 240 430 1121 175–750
Folate (μg/L) <0.8 >20 >20 >2.2
Vitamin A (μmol/L) 0.9 3.4 1.7 1.1–3.5
Vitamin C (μmol/L) 11.6 54.2 12.5 40–100
Vitamin D (nmol/L) 31 72 37 50–75
Vitamin E (μmol/L) – 42.9 32.5 16–35
Vitamin B1 (ngTDP/gHb) – 537 375 275–675
Selenium (μmol/L) 0.39 1.44 0.73 0.6–1.3
Zinc (μmol/L) 10.4 10.6 13.4 8–15
Copper (μmol/L) 16.9 22.0 20.4 12.6–26.7
Low values in bold.
En rules represent no data.

Weight Loss Effects on Vision and Limbs 3
Diagnosis: Nutritional Optic and Sensory Neuropathy

(Also Known as Strachan Syndrome)
Management
Dietary supplementation including multivitamins, thiamine, folic acid and an oral selenium
supplement were prescribed. On discharge, her weight had increased to 68.9 kg with a BMI
of 26 kg/m2. At review three months after presentation, her weight was 76 kg with a BMI of
28.9 kg/m2. Although there had been an interruption in folic acid supplements, her mean cor-
puscular volume subsequently normalised to less than 100 fL (Figure 1.1). Visual acuity had
improved to 6/24 bilaterally and Ishihara plate colour vision to 5/14 on the right and 6/14 on
the left. There was no change in her sensory symptoms. Repeat blood investigations showed
that her vitamin A, C, D and selenium deficiencies had resolved. Folate levels remained nor-
mal, however B12 levels were found to be low and she started regular hydroxycobalamin
injections. Long-term follow-up of her micronutrient status was satisfactory except that vita-
min D and C supplements were required (Table 1.2). She was followed up in the longer term
by a gastroenterologist with a special interest in functional gut disorders and diagnosed with
achalasia.
Comment
A syndrome of optic and peripheral neuropathy, corticospinal tract dysfunction, sensorineu-
ral deafness and ataxia was initially described by Henry Strachan, a British medical officer
working in the West Indies, in 1897. He noticed that the syndrome was prevalent amongst
Jamaican sugarcane workers, and felt at the time that it occurred as a consequence of malaria
infection.
A year later in 1898, Domingo Madán reported a similar syndrome of painful sensory neu-
ropathy and amblyopia, which developed during the trade embargo of the Cuban-Spanish-
American war (1895–8) [1]. This epidemic was named the ‘Amblyopia of the Blockade’. Madán
theorised that alcohol was an aetiological factor, but noticed that there was a social gradient of
the disease, with the majority of patients being working-class females. He raised the possibil-
ity of a nutritional basis for the disease.
Mean corpuscular Folate levels

Treatment MCV Folate level
volume (MCV) fL μg/L
110 18
16
105
Normal folate levels
14
12
100
10
Normal MCV range
8
95
6
90 4
2
85 0
1 2 3 4 5 6 7 8 9 10
Months
Figure 1.1 Effect of folic acid supplements on serum folate levels and mean corpuscular volume.

Table 1.2 Micronutrient levels 10 years after diagnosis
Vitamin or mineral 10 years+ Normal ranges

B12 (ng/L) 767 191–663
Folate (μg/L) 19.8 3.9–26.8
Vitamin A (μmol/L) 2.3 1.1–3.5
Vitamin C (μmol/L) 34.8 >32.0
Vitamin D (nmol/L) 71 50–75
Vitamin E (μmol/L) 34.6 16.0–35.0
Vitamin B1 (ngTDP/gHb) 548 275–675
Selenium (μmol/L) 0.95 0.75–1.46
Zinc (μmol/L) 11.2 9.6–20.5
Copper (μmol/L) 27.9 11.0–25.0
Similar syndromes were then reported in prisoners of war in camps in Japan and the Far
East during the Second World War [2]. A further epidemic occurred in Cuba during the US
embargo, which resulted in a collapse of Cuban trade. Over 50,000 cases of optic and periph-
eral neuropathy were documented in a population of 10.8 million between 1991 and 1994.
Records suggested that 52% of patients had an optic form, with progressive bilateral symmet-
rical loss of central visual function, reduced visual acuity, reduced colour vision and central
fields, whilst 48% had a peripheral neuropathy, or mixed form, with a predominantly length-
dependent sensory neuropathy, but also motor, dorsal column and auditory nerve involve-
ment. Studies of sural nerve biopsies showed predominantly a large fibre axonal neuropathy.
Epidemiological studies found that most of the affected individuals were men between the
ages of 25 and 64 years. The population who had been targeted for nutritional supplementa-
tion before the epidemic (pregnant women, children and the elderly) were minimally affected
[3]. Tobacco use, low animal product and vitamin B intake, irregular meals, poor food avail-
ability, and cassava, sugar and alcohol consumption were identified as risk factors for devel-
opment of the condition [1]. Following the introduction of polynutritional supplements for
the entire population, it was observed that the incidence of new cases declined [3]. Treatment
with high-dose parenteral vitamin B complex, oral vitamins A and E, folic acid and a high
protein diet was associated with a significant improvement in many patients [1].
Nutritional neuropathies have also been reported in anorexia nervosa patients. Similar
syndromes of tropical ataxic neuropathy have been described in Africa and have been attrib-
uted to cyanide intoxication due to chronic cassava ingestion. Reports of outcomes vary. In
Cuba there have been very few reported long-term sequelae. However, in 1955, Charles Miller
Fisher published the results of postmortem studies of 11 Canadian prisoners of war. During
captivity they had complained of a combination of numbness, tingling, pain and weakness
of the hands and feet, poor vision, deafness and mucocutaneous changes. Despite adequate
nutritional supplementation, these patients had residual symptoms and signs of neuropathy
and neuropathological changes up to 10 years after disease onset. Miller Fisher was the first to
propose that until an aetiological factor could be identified, the syndrome should be named
after Strachan.
Strachan syndrome is a rare disorder due to polynutritional deficiency. As there are many
causes of optic neuropathy, consideration of Strachan syndrome may not always be on a dif-
ferential list. However, the macrocytosis, low folate level and optic and peripheral neuropathy

Weight Loss Effects on Vision and Limbs 5
were diagnostic clues in our patient (after excluding transverse myelitis, as can occur in
neuromyelitis optica spectrum disorder/myelin oligodendrocyte glycoprotein antibody-
associated disease).
Strachan syndrome has been reported in association with marked malnutrition and soci-
oeconomic deprivation. The Strachan syndrome patient described here was a 46-year-old
Caucasian woman who was not clinically underweight but had had a dramatic weight loss due
to achalasia. This report emphasises the importance of prompt nutritional supplementation
if considering a diagnosis of Strachan syndrome in a patient who has lost weight and has an
optic and peripheral neuropathy.
References
1 Ordunez-Garcia PO, Nieto FJ, Espinosa-Brito AD, Caballero B. Cuban epidemic neuropathy,
1991 to 1994: history repeats itself a century after the ‘amblyopia of the blockade’. Am J Public
Health. 1996 May;86(5):738–43.
2 Denny-Brown D. Neurological conditions resulting from prolonged and severe dietary
restriction; case reports in prisoners-of-war, and general review. Medicine (Baltimore). 1947
Feb.;26(1):41–113.
3 Thomas PK, Plant GT, Baxter P, Bates C, Santiago Luis R. An epidemic of optic neuropathy and
painful sensory neuropathy in Cuba: clinical aspects. J Neurol. 1995 Oct.;242(10):629–38.
Learning Points
• Low serum folate with macrocytosis can be a clue to nutritional deficiency.
• Nutritional deficiencies may cause an optic and/or peripheral neuropathy known as Strachan
syndrome.
• Food embargoes have been implicated in large outbreaks of Strachan syndrome.
• Functional gastrointestinal problems can cause nutritional deficiencies.
Patient’s Perspective
1. What was the impact of the condition?
a. Physical (e.g. job, driving, practical support)
Loss of power or muscle control in my legs and arms and poor vision.
b. Psychological (e.g. mood, future, emotional well-being)
Depression – lack of social engagement, loss of friends to socialise with, poor appetite, feeling lost and
alone.
c. Social (e.g. meeting friends, home)
No socialising due to fear of falling has meant disconnection with friends.
2. What could you no longer do after developing Strachan syndrome?
I find it difficult to do a lot of housework, such as making beds or hoovering – due to lack of power.
3. Was there any change for you because of the diagnosis?
Lack of socialising has been the biggest change. However, everyday activities also require more effort.
In addition, I have had to give up wearing heels and I have had to give up driving due to my poor
eyesight.
4. What is/was the most difficult aspect of the condition?
The feeling of helplessness and having to rely on others for things I previously could do for myself, such
as dressing/hair washing.
5. Was any aspect of the experience good or useful? What was that?
Not applicable. It has all been a negative experience.
6. What do you hope for in the future for your condition (Strachan syndrome)?
More understanding of the condition (Strachan syndrome) and hopefully earlier diagnosis.

2 Adult-Onset Visual Loss
CASE
History
A 54-year-old man and taxi driver developed progressive loss of vision over four months.
Initially it was thought that he had toxic amblyopia as he drank 14–25 pints of beer per week.
He did not smoke cigarettes. However, the diagnosis was revised as a family history of a neuro-
logical condition emerged.
Examination
Visual acuity in each eye was reduced to hand movements, with no improvement from pin-
hole testing. His right optic disc was swollen with haemorrhage. The left optic disc margin was
indistinct. Otherwise, his neurological examination was normal.
Investigations
Vitamin B12 and folate were normal. Micronutrients (copper, selenium and zinc) levels were
normal. Anti-myelin oligodendrocyte glycoprotein and anti-neuromyelitis optica IgG aqua-
porin 4 antibodies were negative. MRI of brain, orbits and spine revealed no focal abnormal
lesion.
Management
He received supportive measures for visual loss. He stopped drinking all alcohol. He had
compensated liver cirrhosis, IgA nephropathy and hypertension.
A diagnostic test was performed.

Diagnosis: Leber Hereditary Optic Neuropathy

A mitochondrial mutation m.11778G>A, one of the three common causes of Leber heredi-
tary optic neuropathy, was identified. Charles Bonnet syndrome developed. He was registered
blind. Optic atrophy ensued.
Comment
Measuring Visual Acuity
Herman Snellen, a Dutch ophthalmologist, devised the Snellen chart in 1862. The usual
Snellen chart has 11 lines of block letters – C, D, E, F, L, O, P, T and Z – with specific geometry
(the thickness of the lines equals the thickness of the white spaces between the lines and the
thickness of the gap in the letter ‘C.’ The height and width of the letter is five times the thick-
ness of the line.
According to BS 4274–1:2003, only the letters C, D, E, F, H, K, N, P, R, U, V and Z should
be used for the testing of vision as these letters have equal legibility.
At 6 metres distant from the patient, the letters of the 6/6 (or 20/20 in the USA) line sub-
tend five minutes of arc. The minimum standard of vision for driving in the UK is between 6/9
and 6/12, equivalent to reading a number plate from a distance of 20 metres on a car registered
since 2001 (Figure 2.1).
A logarithm (base 10) of the minimum angle of resolution (LogMAR) chart is designed for
a more accurate estimate of visual acuity. An individual who can resolve details as small as one
minute of visual angle scores LogMAR 0 (as base 10 logarithm 1 is 0). Figure 2.1 provides Snel-
len and LogMAR equivalent acuity readings. Clinical research trials tend to use the LogMAR
chart because of its better accuracy.
Figure 2.1 Schematic representation of a Snellen chart with Snellen and LogMAR acuities.

Adult-Onset Visual Loss 9
Criteria to Be Certified Blind

To be certified severely sight impaired (blind), one of the following criteria is required:
• visual acuity of less than 3/60 with a full visual field;
• visual acuity of between 3/60 and 6/60 with a severe reduction of field of vision, such as
tunnel vision;
• or visual acuity 6/60 or better but with a very reduced field of vision.
Differential Diagnosis of Bilateral Optic Neuropathy

There is a large differential diagnosis for optic neuropathy, which can be mistakenly attributed
to demyelinating optic neuritis. Some common causes of optic neuropathy are listed in Table
2.1.
Pathophysiology and Epidemiology of Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disease that causes pro-
gressive loss of vision, usually in the second and third decades of life. Although first described
in 1848 by Albrecht von Graefe, LHON was subsequently reported by Theodore Leber in
Table 2.1 Differential diagnosis of an optic neuropathy (broad mechanisms of disease)
Glaucoma
Raised intracranial pressure (papilloedema)
Inflammatory
• Idiopathic inflammatory optic neuritis (associated with multiple sclerosis)
• Neuromyelitis optica
• Systemic inflammatory and autoimmune diseases
• Infectious diseases
Vascular
• Anterior or posterior
• Arteritic or non-arteritic
• Post-radiation therapy
Compressive or infiltrative
• Neoplastic
• Non-neopalstic
Paraneoplastic
Toxic
Nutritional
Hereditary
Traumatic
Optic nerve head drusen
Congenitally anomalous optic nerve
Glaucoma is by far the most common cause of optic neuropathy and a leading cause of
blindness; inflammatory optic neuritis is the most common subacute optic neuropathy
in young people; non-arteritic anterior ischaemic optic neuropathy is the most
common acute optic neuropathy in patients older than 50 years.
Adapted from Biousse and Newman [1] with permission from Elsevier.

1871. Three common mutations in the mitochondrial genome (m.3460G>A, m.11778G>A

and m.14484T>C) affect complex I of the mitochondrial respiratory chain. These mutations
account for over 90% of patients with LHON in Europe and North America. The m.11778G>A
mutation (70% of Northern European and 90% of Asian cases) causes more severe disease.
There is a defect in the synthesis of adenosine triphosphate and oxygen-free radicals damage
the retinal ganglion cell layer. In Northern Europe prevalence of LHON is at least 1 in 30,000
(3.2–4.4 per 100,000).
A lower heteroplasmy rate correlates with less disease manifestation. In addition, pen-
etrance of LHON varies with sex; 50% of males and just 10% of female carriers develop vis-
ual loss. Environmental factors, particularly smoking, have been implicated in visual loss in
LHON [2]. Alcohol has a modifying effect, excess consumption being associated with ear-
lier visual loss. Mitochondrial DNA-haplotype background is also thought to influence the
occurrence and severity of visual loss in LHON.
In 75% of patients, acute central visual loss is unilateral before the other eye is affected
weeks to months later. In the reminder (as in our patient), the acute visual loss begins bilat-
erally. The visual failure is painless. LHON has associations with multiple systems. Tremor,
neuropathy, movement disorders and a leukoencephalopathy mimicking multiple sclerosis
have all been described in LHON.
Treatment Research
Idebenone is an antioxidant that inhibits lipid peroxidation. It is a short chain benzoquinone
with mitochondrial effects that activate viable but inactive retinal ganglion cells. An open-
labelled study and a randomised controlled trial (the RHODOS trial) assessed idebenone.
The primary outcome in the RHODOS trial was not met (change from baseline to 24 weeks
in best visual acuity). However, a sub-group analysis in patients with discordant visual acu-
ity found improvements in visual acuity. In the RHODOS trial, 12 out of 61 patients taking
idebenone (300 mg tid) who could read no letters on the chart at baseline were able to read at
least five letters by week 24 compared to 0 out of 29 in the placebo group (p = 0.008). The trial
demonstrated that patients with m.11778G>A and m.3460G>A mutations had the largest
treatment effect. The m.14484T>C mutation has a high spontaneous recovery rate. Idebenone
had minimal side effects [3].
An expanded access programme has suggested idebenone 900 mg/day was associated
with clinically relevant recovery in nearly half of patients (46%).
The Scottish Medicines Consortium (SMC No. 1226/17) indication for idebenone
restricts use of idebenone to patients with LHON who are not yet blind. In 2019, NHS
England deemed that idebenone did not have sufficient evidence for the treatment of
patients with LHON.
However, genetic treatment of LHON is emerging, which may be less controversial.
Lenadogene nolparvovec (rAAV2/2-ND4) is an adeno-associated viral vector that has
the modified cDNA encoding human wild-type mitochondrial ND4 protein, the defect in
m.11778G>A LHON. Patients with LHON due to an m.11778G>A mutation were enrolled
if visual loss was 12 months or less. A single intravitreal injection of lenadogene nolparvovec
has shown sustained improvement in best corrected visual acuity in both eyes and improve-
ment in quality of life in two phase 3 trials [4]. Gene therapy may become an important treat-
ment for LHON if efficacy and safety can be maintained.

Adult-Onset Visual Loss 11
References
1. Biousse V, Newman NJ. Diagnosis and clinical features of common optic neuropathies. Lancet
Neurol. 2016;15(13):1355–67.
2. Kirkman MA, Yu-Wai-Man P, Korsten A et al. Gene-environment interactions in Leber
hereditary optic neuropathy. Brain. 2009;132(9):2317–26.
3. Catarino CB, von Livonius B, Priglinger C et al. Real-world clinical experience with idebenone in
the treatment of Leber hereditary optic neuropathy. J Neuro-Ophthalmology. 2020;40(4):558–65.
4. Biousse V, Newman NJ, Yu-Wai-Man P et al. Long-term follow-up after unilateral intravitreal
gene therapy for Leber hereditary optic neuropathy: the RESTORE study. J Neuro-Ophthalmology.
2021;41(3):309–15.
Learning Points
• Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder that can cause
progressive, painless visual loss more often in males than females.
• In LHON, environmental factors such as alcohol and smoking play a role in visual loss.
• Genetic treatment has shown early promise in improving vision in patients with recent
(<12 months) visual loss due to LHON.
1. What was the impact of the condition on you?
Shock, fear and how I will I be able to cope with loss of my sight.
I became very depressed. I did not want to leave the house and I had a fear of losing my cane.
I was nervous about meeting people and embarrassed eating out in restaurants etc.
2. What can you no longer do?
I had to stop driving. I can no longer watch television, read newspapers or go to Gaelic matches, which
I loved to attend.
3. Was there any other change for you due to your medical condition?
Yes, I developed Charles Bonnet syndrome. This had a major impact and was very disturbing as I had
visual hallucinations of machinery, animals, people from period times, both at home and when I was
outside.
4. What is/was the most difficult aspect of the condition for you?
Learning to adapt to living my life in a new way.
Yes, eventually after a few years I became more confident dealing with all the above-mentioned
changes.
6. What do you hope for in the future for your condition?
It would be good if medicine improved to maybe be able to enhance people’s lives with sight loss.

3 A BEE of a Syndrome
CASE
History
A 44-year-old right-handed female driver developed a new onset moderately severe headache
with vomiting. She attended hospital and had a CT scan of her brain and a lumbar puncture;
both were reported as normal. She was discharged from hospital but over the next week the
headaches became more severe and vomiting recurred. Then, 11 days after the onset of head-
ache, she developed slurred speech and impaired concentration. She giggled inappropriately
and became confused. Her condition fluctuated but did not return to normal. She had no oral
or genital ulcers but had noticed decreased hearing on her right side. She was re-admitted to
hospital and a neurological opinion was sought.
She had two children. She did not smoke cigarettes but drank one bottle of wine at
weekends.
Examination
She had no rash and no mouth ulcers. She was dysphasic and encephalopathic, smiling out
of context. She knew the month but not the day. She recognised that she was in hospital. She
could not explain a doctor’s role. She had decreased hearing on the right. Clinical examina-
tion of her eyes was normal. The remaining cranial nerves were normal. Neurological exami-
nation of her limbs was normal. Her cardiovascular examination was normal.
Clinical differential diagnosis from the neurological consultation included:
1. an immune-mediated brain, ear and eye (BEE) syndrome such as Susac syndrome
2. autoimmune encephalitis
3. infective encephalitis, Lyme disease or tuberculosis
4. nutritional encephalopathy
5. a demyelinating condition such as multiple sclerosis
6. vasculitis
7. a connective tissue disorder
8. a mitochondrial disorder
Investigations
An MRI scan of the brain demonstrated callosal lesions, left thalamic (pulvinar) and bilateral
cerebellar lesions (Figure 3.1A–3.1D). There were also lesions in the posterior pons at the level
of the medial longitudinal fasciculus and rostral midbrain. Following contrast, there was no
abnormal enhancement. An MRI of the spine revealed no definite lesions.
13

Figure 3.1 A (A) sagittal and (B) axial T2 FLAIR MRI scan of the brain, showing corpus callosal lesions. An axial MRI
brain showing pulvinar lesion in (C) the left thalamus and (D) bilateral cerebellar lesions. Fluorescein angiography
(E) shows a BRAO (arrow). (F) Audiometry demonstrates a right hearing deficit more prominent at lower
frequencies.
She had two lumbar punctures. The cerebrospinal fluid (CSF) findings are shown in
Table 3.1.
An EEG showed a marked excess of slow waves, most notably over the temporal regions
but affecting both hemispheres in keeping with an encephalopathy.
Tests for antibodies to N-methyl-D-aspartate receptor (NMDAR), myelin oligoden-
drocyte glycoprotein (MOG), neuromyelitis optica (NMO) aquaporin 4 and voltage-gated
potassium channel (leucine-rich, glioma-inactivated 1 (or LGI1) and contactin-associated
protein-like 2 (or CASPR2)) in blood and CSF were all negative. A nuclear autoantibody
screen was negative. The thyroid profile, ammonia, B12 and folate levels were normal. Fluor-
oscein angiography showed a branch retinal artery occlusion (BRAO) (Figure 3.1E). Audi-
ometry revealed right hearing loss, worse at lower frequencies (Figure 3.1F).

A BEE of a Syndrome 15
Table 3.1 CSF findings
Measurement (normal range) LP 1 LP 2 (two weeks later)

Opening pressure (6–25 cmCSF) 18 cmCSF 29 cmCSF
CSF white cells (<5/μL) 1 1
CSF red cells 107 65
CSF glucose/serum glucose 3.4 mmol/L/5.5 mmol/L 3.0 mmol/L/9.0 mmol/L
CSF protein (<0.4g/L) 0.53 g/L 1.55 g/L
Oligoclonal bands Not done Not detected
Enterovirus PCR Negative Negative
Herpes simplex virus 1 and 2 and varicella zoster Negative Negative
virus PCR
Neisseria meningitidis/Streptococcus Negative Negative
pneumoniae/Haemophilus influenza
Parechovirus PCR Negative Negative
NMDAR antibody Not done Negative
Voltage-gated potassium channel antibodies Not done Negative
(LGI-1 and CASPR2)

Diagnosis: Susac Syndrome
Comment
Susac syndrome is an immune-mediated, pauci-inflammatory, occlusive microvascular
endotheliopathy or basement membranopathy that affects the brain, retina and inner ear [1].
Brain manifestations include cognitive, psychiatric, headache and focal neurological deficits.
There have been very few epidemiological studies; one study from Austria reported an inci-
dence of 0.024 per 100,000 per year (95% CI 0.010–0.047).
Differential Diagnosis
There is a wide range of differential diagnoses for Susac syndrome, but the triad of clinical
features of encephalopathy, deafness and BRAO suggests Susac syndrome. There is a need for
fluorescein angiography to confirm BRAO because BRAO can be asymptomatic. The con-
dition may be radiologically and clinically diagnosed as multiple sclerosis because multiple
sclerosis is a much more common neurological disorder in young adults. Clinicians, however,
should think of other causes, particularly if the brain, ear and eye are involved. Recognised
immune-mediated BEE syndromes include multiple sclerosis, antiphospholipid syndrome,
neurosarcoidosis, systemic lupus erythematosus, neuromyelitis optica spectrum disorder,
Behçet disease, Vogt–Koyanagi–Harada disease (systemic granulomatous autoimmune dis-
ease against melanocyte-containing tissues – uvea, retina, leptomeninges, inner ear and skin),
Cogan syndrome (an autoimmune disease affecting eye, audio and vestibular apparatus with
antibodies to connexion 26, which can also cause meningitis, encephalitis, psychosis, seizures
and cerebral infarction) and Susac syndrome.
History of Susac Syndrome

Susac syndrome was named after John Susac (1956–2012) following his report of the con-
dition in 1979. The condition had previously been described as small infarction of cochlear,
retinal and encephalic tissue (SICRET) syndrome or retinocochleocerebral vasculopathy.
Susac was criticised when he argued that this neurological disorder was not multiple
sclerosis. Involvement of the retina, cochlea and brain explains the clinical triad of visual loss
due to BRAOs, sensorineural hearing loss (in the low to moderate range frequencies) and
encephalopathy. The encephalopathy includes cognitive impairment, psychiatric disturbance,
headache, seizures and focal neurological deficits. More than 300 cases had been described by
2013, but most patients do not present with the full clinical triad. Partial presentations may have
a role in delaying diagnosis. In addition, vestibular abnormalities are very common in Susac
syndrome. The mechanism of the immune-mediated endotheliopathy is not clear.
Pathophysiology of Susac Syndrome

Anti-endothelial cell antibodies in serum of patients with Susac syndrome have been
identified, although their exact role is unclear. However, in 2019, a CD8+ T cell-mediated
endotheliopathy was identified as a mechanism in the neuro-inflammation of Susac syn-
drome [2]. The authors of this paper revealed that blocking T-cell adhesion (with anti-α4
integrin – a transmembrane heterodimer that acts as an adhesion receptor for extracellular
ligands) not only improved the disease in a preclinical mouse model, but also resulted in less
severe disease in four patients when treated with natalizumab, albeit along with other therapy.
Clinical trial data are awaited.

A BEE of a Syndrome 17
Diagnostic Confirmation
Retinal fluorescein angiography can confirm arterial occlusion in the region of suspected
BRAOs. Asymptomatic BRAOs and vessel-wall hyperfluorescence remote from bifurcations
where emboli may lodge can confirm diffuse endothelial-cell damage.
Pathognomonic MRI Findings in Susac Syndrome

The central corpus callosum is supplied by small-calibre blood vessels. MRI lesions in the
centre of the corpus callosum are referred to as ‘snowball’ lesions. Central callosal ‘icicle’ and
‘spoke’ lesions in contact with the roof of the corpus callosum support a diagnosis of Susac
syndrome; these are said to differ in location from other inflammatory conditions including
multiple sclerosis. A ‘string of pearls’ appearance from microinfarcts in the internal capsule
has also been described. Common areas of MRI brain abnormalities include periventricular
regions, centrum semiovale, cerebellum, brainstem and middle cerebellar peduncles. Many
of these lesions were identified in our patient (Figure 3.1). Grey and white matter lesions often
enhance. Widespread axonal damage has been recognised.
Suggested diagnostic criteria are based on the recognised triad of features in Susac syn-
drome [3]. The European Consortium classification for a definite diagnosis of Susac syn-
drome requires a full triad of brain, ear and eye involvement. Brain symptoms include new
cognitive impairment and/or behavioural changes and/or new focal neurological symptoms
and/or headache with hyperintense, multifocal small round lesions on a T2 FLAIR MRI of the
brain, at least one of which must be in the corpus callosum ‘snowball.’ Retinal findings include
BRAOs or arterial wall hyperfluorescence, while vestibulocochlear symptoms include tin-
nitus and/or hearing loss and/or vertigo in the presence of hearing loss documented on an
audiogram [3]. A probable diagnosis of Susac syndrome exists if any two of the three features
are present.
Management of Susac Syndrome

Clinical experience suggests that therapy targeting both B cells and T cells has efficacy but
there is a lack of randomised controlled trials and prospective treatment studies [1]. The first
aim of therapy is to induce remission with intravenous methylprednisolone followed by a slow
taper of oral glucocorticoid therapy over several months. For severe disease, rituximab has
also been used. Next, glucocorticoid-sparing maintenance immunotherapy involves rituxi-
mab, mycophenolate or azathioprine. Expert recommendations suggest acute treatment for
several months to 2.5 years. A gradual withdrawal of therapy may be considered if the disease
has been inactive for 24 months. Lack of long-term data necessitates long-term follow-up. A
group in Cleveland, US has extensive experience and has recommended treatment based on
a qualitative severity scale [1].
Follow-up management involves serial audiometry, fluorescein angiography and MRIs of
the head.
References
1. Rennebohm RM, Asdaghi N, Srivastava S, Gertner E. Guidelines for treatment of Susac
syndrome: An update. Int J Stroke Off J Int Stroke Soc. 2020;15(5):484–94.
2. Gross CC, Meyer C, Bhatia U et al. CD8+ T cell-mediated endotheliopathy is a targetable
mechanism of neuro-inflammation in Susac syndrome. Nat Commun. 2019;10(1):5779.

3. Kleffner I, Dörr J, Ringelstein M et al. Diagnostic criteria for Susac syndrome. J Neurol Neurosurg
Psychiatry. 2016;87(12):1287–95.
Learning Points
• Susac syndrome causes deafness, branch retinal artery occlusions and an encephalopathy.
• Susac syndrome is an immune-mediated BEE syndrome.
• Corpus callosal snowball lesions on MRI brain scanning are found in Susac syndrome.
• Pathophysiology of Susac syndrome may be a T-cell mediated endotheliopathy.
• Empirical aggressive initial immunosuppressant treatment with high-dose corticosteroids is
often used.
1. What was the impact of the condition?
Susac syndrome took away my independence as I was totally confused in all aspects of life. I could not
do the following tasks:
drive or work;
care for my home or my teenage daughter;
make financial decisions as I didn’t comprehend what was required for me; and
initially, read or write.
I needed full-time care, which I received from my family, as I was not able to bathe, make food, eat/
feed myself or shop for basic groceries. I suffered continuous exhaustion and headache.
b. Psychological (mood, future, emotional well-being)
I found myself in a very dark place, often having suicidal thoughts. I suffered a continual low mood,
having many tearful episodes. I have been short-tempered with many mood swings. Overall, I would
say depressed with PTSD. I have anxiety attacks daily.
I have felt very unsure of myself, losing all confidence in going anywhere alone. I feel isolated and
paranoid as I didn’t want anyone to see me like ‘this.’ ‘This’ meaning – a few stone heavier. I felt people
were talking about me, as they may not have recognised me. I also was not fit for visitors coming to
me.
2. What can or could you not do because of the condition?
Initially I didn’t recognise my closest family and friends. I could not make any decisions, financial
or for daily tasks. I couldn’t read or understand the content of letters or process any information.
Managing appointments was left to others, as was cooking, laundry and shopping.
Yes, I developed vertigo and tinnitus. I found my eyesight impaired and lost my hearing on the right.
I also suffer from joint pain and generalised body pains daily. My sleeping pattern is also disturbed
and, due to my medication my toileting habits are also unpredictable.
Trying to adjust to the new me. I struggle daily with the effects of Susac syndrome. I feel like I have lost
myself to this condition. My life has changed dramatically as I still cannot function anywhere near the
way I did pre-Susac’s.
5. Was any aspect of the experience of the condition good or useful? What was that?
In a word – no. I can’t find anything positive about this condition other than the care I have received.
6. What do you hope for in the future for people with this condition?
My hope is that there may be a treatment available that doesn’t impact daily life or even a cure in the
near future. Maybe more awareness and research would be good too.

4 Multiple Problems
CASE
History
A 23-year-old right-handed student presented with a one-year history of unsteadiness and a
six-month history of urinary and bowel urgency with incontinence. Four weeks before hospi-
tal admission, she also had a change in the vision from her right eye, only seeing the periphery
of the visual field. Three weeks prior to hospital admission, she had right-hand numbness and
weakness and was admitted to hospital when she developed left-leg weakness and numbness.
Past medical history included depression, breast augmentation and mastoplexy. She also
had B12 deficiency. She had no history of miscarriage, oral or genital ulcers, deep venous
thrombosis or pulmonary emboli.
Medication was sertraline 100 mg/day and B12 replacement.
Examination
She was alert, orientated and systemically stable. She had marked truncal ataxia. Visual acuity
on a Snellen chart was 6/6-2 on the right and 6/6 on the left, both unaided. She had normal
upper limb tone and strength. Tone was normal in the legs but there was a pyramidal distribu-
tion of weakness in her left leg (hip flexion, knee flexion and ankle dorsiflexion grade 4/5). She
had brisk reflexes and bilateral ankle clonus, more sustained on the left. Joint position sense,
pinprick and cold sensation were intact.
Investigations
Full blood count, electrolytes, liver function tests, thyroid profile, B12 and folate levels
and nuclear autoantibody screen were all normal. HIV, syphilis, Lyme serology, HTLV-1,
anticardiolipin antibodies, lupus anticoagulant and angiotensin converting enzyme tests
were negative or normal.
An MRI of the brain showed multiple periventricular lesions. An MRI of the spine showed
a medulla lesion and multiple spinal lesions (Figure 4.1).
Lumbar puncture results are shown in Table 4.1.
19

Figure 4.1 (A) Non-contrast axial T2 FLAIR MRI scan of brain shows multiple bilateral
periventricular and some subcortical lesions. (B) A T2 sagittal MRI scan of the spine
demonstrates a round medullary lesion and at least five ‘droplet-like’ lesions in the spinal cord.
Table 4.1 Blood and cerebrospinal fluid investigation results
Measurement (normal range) Value

Opening pressure (6–25 cmCSF) 20 cmCSF
White cell count (<5/μL) 3/μL
Red cell count 4/μL
Cerebrospinal fluid protein (<0.4g/L) 0.44 g/L
Cerebrospinal fluid glucose 3.2 mmol/L
Serum glucose 5.5 mmol/L
Oligoclonal bands restricted to cerebrospinal fluid Positive
Lupus anticoagulant/anti-beta-2-glycoprotein antibody/ Negative
anticardiolipin antibody
Neuromyelitis optica IgG aquaporin 4 antibody Negative
Myelin oligodendrocyte glycoprotein antibody Negative
Anti-gastric parietal cell antibody Negative
Anti-intrinsic factor antibody Negative
John Cunningham (JC) virus Negative

Multiple Problems 21
Diagnosis: Relapsing-Remitting Multiple Sclerosis
Management
A five-day course of intravenous methylprednisolone (500 mg/day) was given, which was
associated with a good improvement in her left leg strength. Subsequently, monthly natali-
zumab was started and well tolerated.
Over the next four years, she remained clinically and radiologically stable, with no evi-
dence of new demyelinating lesions or progressive multifocal leucoencephalopathy. However,
in the fourth year after her diagnosis, she had three episodes of generalised seizure activity. A
repeat MRI brain scan had shown no new lesions. An EEG demonstrated fairly frequent slow
activity over the left temporal region. She was treated with lamotrigine. Three years on, she
has been seizure-free and continues on natalizumab and lamotrigine.
Comment
The Epidemiology of Multiple Sclerosis
Multiple sclerosis is an immune-mediated disease of the central nervous system that affects
mostly young individuals and, increasingly, females. Epidemiological studies have demonstrated
a north-south gradient in the incidence rate of the disease. Lack of vitamin D, particularly from
sunlight, may play an aetiological role in multiple sclerosis but evidence of benefit from supple-
mentary oral vitamin D (prevention of relapse) has not been consistently identified. Infection
with Epstein-Barr virus has been associated with a markedly increased risk of developing multiple
sclerosis. There is now better evidence for a causal role of Epstein-Barr virus in multiple sclerosis.
The Clinical Presentation and Pathology of Multiple Sclerosis

Classically, multiple sclerosis has been classified into relapsing-remitting multiple sclerosis,
clinically isolated syndrome, radiologically isolated syndrome, primary progressive multiple
sclerosis and secondary progressive multiple sclerosis. Fred Lublin then added the presence
of active and non-active descriptions to each of the subtypes [1]. Activity is determined by
clinical relapse and/or MRI activity. Progression is measured by an annual clinical evaluation.
Four stages of pathology have been recognised in multiple sclerosis [2].
Although multiple sclerosis has been classified as an inflammatory disorder of white mat-
ter, acute demyelinating lesions can occur with neuronal loss and meningeal inflammation.
Recognised Pathological Stages of Multiple Sclerosis

Pattern 1 (15%)
Active demyelination and remyelination. Oligodendrocyte precursor cells
Variable loss of oligodendrocytes at lesion edge
Lymphocytes, activated microglia/macrophages
Pattern 2 (60%)
Active demyelination and remyelination. Oligodendrocyte precursor cells
Variable loss of oligodendrocytes at lesion edge
Immunoglobulin and complement deposition on myelin and on myelin debris within
macrophages
Inflammatory cells

Pattern 3 (24%)
Active demyelination (preferential loss of myelin-associated glycoprotein); no
remyelination
Extensive oligodendrocyte apoptosis throughout lesion and beyond
Initial damage to parts of the oligodendrocyte most distal from its cell body
Inflammatory cells
Pattern 4 (1%)
Profound oligodendrocyte loss in periplaque white matter
Bladder Symptoms in Multiple Sclerosis

Bladder symptoms are frequent in multiple sclerosis. Bladder storage symptoms include
urinary frequency, urgency with or without incontinence. Voiding problems manifest with
hesitancy, poor or interrupted urinary stream, sensation of incomplete emptying and double
voiding. Both types of bladder symptoms can develop in multiple sclerosis. Lesions above
the pons can cause storage symptoms due to loss of inhibition on the detrusor muscle. Spinal
lesions (often present in multiple sclerosis) can cause a mixture of storage and voiding symp-
toms. Lesions in the conus medullaris may cause voiding symptoms. A post-void residual over
100 ml may require clean intermittent self-catheterisation. Otherwise, an anti-cholinergic
drug is indicated, ideally with more muscarinic M3 specificity for the bladder and less central
muscarinic effects on cognition.
Epilepsy and Multiple Sclerosis

There is a positive association between multiple sclerosis and epilepsy (as observed in our
patient). The pooled prevalence of epilepsy among patients with multiple sclerosis is 3% com-
pared to 0.4–1.2% in the general population.
Criteria for Diagnosing Multiple Sclerosis (a Will Rogers Phenomenon)

Allowing a disease to be diagnosed at an earlier stage can seem to improve outcome when
measured as disability or survival. The 2017 revised McDonald criteria for multiple sclerosis
[3] lead to diagnosis of more patients with less active multiple sclerosis compared to previous
iterations of the McDonald criteria. The 2017 McDonald criteria are best used in populations
in which multiple sclerosis is relatively common and in patients in whom there is a typical
presentation.
MRI evidence of dissemination in space requires two of the following:
• one or more periventricular lesions
• cortical or juxtacortical lesion
• infratentorial lesion
• spinal cord lesion.
Dissemination in time requires one of the following criteria:
• a second attack/relapse
• new lesions on a follow-up MRI scan
• simultaneous enhancing and non-enhancing lesions on an MRI scan
• restricted oligoclonal bands in the cerebrospinal fluid.

Table 4.2 The 2017 McDonald criteria for diagnosing relapsing-remitting multiple sclerosis
Number of clinical Number of lesions with Additional data needed for a

attacks (separated objective clinical evidence diagnosis of multiple sclerosis
by 30 days)
≥2 ≥2 None
≥2 1 (as well as clear-cut historical None
evidence of a previous attack
involving a lesion in a distinct
anatomical location†)
≥2 1 DIS –clinical episode at another site or MRI
1 ≥2 DIT by clinical episode, MRI or restricted
oligoclonal bands
1 1 DIS by further clinical episode at another site
or by MRI
and
DIT by further clinical episode, by MRI or
restricted oligoclonal bands
DIS= disseminated in space; DIT = disseminated in time

Adapted from Thompson et al. [3] permission from Elsevier.
Table 4.2 highlights different scenarios in which multiple sclerosis can be diagnosed. The
original 1965 Schumacher criteria were purely clinical (patients 10–50 years old, attacks last-
ing at least 24 hours, separated by at least a month, or for progressive multiple sclerosis a slow
or stepwise progression over at least six months, and evidence of white matter disease in two
or more distinct sites) and were more restrictive than current criteria. Earlier and therefore
milder disease is now recognised as multiple sclerosis. Aware of the shortcomings of the revi-
sion, the authors stated that neurologists should ‘recognise that the McDonald criteria were
not developed to differentiate multiple sclerosis from other conditions but to identify mul-
tiple sclerosis or a high likelihood of the disease in patients with a typical clinically isolated
syndrome once other diagnoses have been deemed unlikely’ [3].
Accurate Diagnosis of Multiple Sclerosis

Accurate diagnosis of multiple sclerosis relies on both an appropriate history and examin-
ation findings suggestive of demyelination with correct interpretation of neuroimaging. The
National Academy of Medicine (previously known as the Institute of Medicine) has empha-
sised the ‘moral, professional and public health imperative’ to improve the diagnostic process
[4]. An incorrect diagnosis of multiple sclerosis can lead to harmful consequences as some
of the disease-modifying therapies licensed for multiple sclerosis can exacerbate another
demyelinating disease – neuromyelitis optica. Academic centres suggest that misdiagnosis of
multiple sclerosis can include conditions such as fibromyalgia, non-specific or non-localising
neurological symptoms with an abnormal MRI and neuromyelitis optica spectrum disorder.
There is a large differential diagnosis for multiple sclerosis, but there are a number of con-
ditions to be considered from migraine to sarcoidosis, anti-myelin oligodendrocyte glyco-
protein antibody-associated disease, neuromyelitis optica spectrum disorder, lymphoma,
autoimmune glial fibrillary acidic protein astrocytopathy (a rare disorder associated with
steroid-responsive encephalitis, meningitis, myelitis or meningoencephalitis first described
in 2016) and Fabry disease.

While neuromyelitis optica is a recognised cause of longitudinal extensive myelitis

(defined on a spinal MRI scan as a lesion extending over three or more vertebral segments),
such spinal lesions can occur in 3% of patients with multiple sclerosis; 0.7% of multiple sclero-
sis patients can present with longitudinally extensive myelitis. Other causes of longitudinally
extensive myelitis include myelitis associated with systemic autoimmunity such as systemic
lupus erythematosus, infectious (HIV, syphilis, tuberculosis) or paraneoplastic myelitis, met-
abolic (B12 or copper deficiency) and vascular causes (spinal cord infarction).
History of Disease-Modifying Treatments in Multiple Sclerosis

Over 20 drugs have been approved and are currently used as disease-modifying treatments
for relapsing-remitting, primary progressive and secondary progressive multiple sclerosis
(Table 4.3). Primary progressive multiple sclerosis and secondary progressive multiple scle-
rosis have fewer disease-modifying treatments, possibly reflecting a different pathologi-
cal process. Ocrelizumab may be effective in reducing progression in primary progressive
multiple sclerosis. For relapsing-remitting multiple sclerosis, the less effective and earlier-
licensed drugs (glatiramer acetate, interferon beta-1b and interferon beta-1a) appear to
have safer profiles and require less monitoring than subsequent oral and infusion therapies.
Siponimod is used to treat active (relapses or MRI showing new or growing lesions) sec-
ondary progressive multiple sclerosis. Autologous haemopoietic stem cell transplantation
(aHSCT) is a relatively new treatment for patients with highly active relapsing-remitting
multiple sclerosis that has not responded to disease-modifying treatment. As treatment-
related mortality from aHSCT has declined to less than 1%, future robust evidence of
efficacy may result in more use of aHSCT.
Table 4.3. Some disease-modifying treatments in multiple sclerosis
Name of drug Year of license Mode of Mode of action

administration
Interferon beta-1b 1995 Subcutaneous Alters pro- and anti-inflammatory
agents in the brain, decreasing
inflammatory cell access across the
blood–brain barrier
Interferon beta-1a 1997 Intramuscular Alters pro- and anti-inflammatory
agents in the brain, decreasing
inflammatory cell access across the
blood–brain barrier
Mitoxantrone 2001 Intravenous Intercalation of DNA, preventing
repair and inhibiting B and T cell
proliferation
Glatiramer acetate 2001 Subcutaneous Induction of anti-inflammatory
antigen-presenting cells
Natalizumab 2006 Intravenous or Inhibition of α4β1 integrin, a
subcutaneous selective adhesion molecule
blocking VCAM-1 and leukocyte
migration across the blood–brain
barrier
Fingolimod 2011 Oral Sphingosine 1-phosphate receptor
modulator – prevents lymphocytes
entering the central nervous system

Table 4.3. (cont.)
Name of drug Year of license Mode of Mode of action

administration
Teriflunomide 2013 Oral Dihydro-orotate dehydrogenase
inhibitor, a key mitochondrial
enzyme in pyrimidine synthesis,
leading to a reduction in
proliferation of activated T and B
lymphocytes
Alemtuzumab 2013 Intravenous infusion Monoclonal antibody-depleting
CD52-expressing T and B cells
Dimethyl fumarate 2014 Oral Enhances nuclear factor erythroid
2 related factor 2 transcriptional
pathway and inhibits nuclear factor
kappa B
Cladribine 2017 Oral Inhibits DNA polymerase and
ribonucleotide reductase, depleting
T and B lymphocytes
Ocrelizumab 2018 Intravenous infusion Selectively targets CD20-expressing
B cells
Autologous 2019–first RCT Intravenous Re-diversification of the T cell
haemopoietic stem repertoire
cell transplant
Siponimod 2020 Oral Sphingosine 1-phosphate receptor
modulator – prevents lymphocytes
entering the central nervous system
Ofatumumab 2021 Subcutaneous Selectively targets CD20-expressing
injection B cells
An MRI scanning surveillance system allows confirmation of escalating disease burden

with or without clinical relapses. Such scanning may be facilitated by artificial intelligence or
computer-aided design in order to identify patients in need of escalation of disease-modifying
therapy. The ultimate goal of therapy is safety and no evidence of disease activity (NEDA).
Earlier treatment with more efficacious drugs appears to lessen long-term disability. Rates of
NEDA for aHSCT between 61 and 92% at two years have been recorded.
The history of two disease-modifying drugs in multiple sclerosis is summarised in the
next section.
Natalizumab and Progressive Multifocal Leucoencephalopathy

Natalizumab is a humanised anti-α4 integrin monoclonal antibody blocking the binding of α4β1
and α4β7 integrins to their endothelial receptors in order to reduce inflammation. Natalizumab
also inhibits the interaction of α4-positive leucocytes, fibronectin and osteopontin. Following
interim data analysis of two phase three trials (AFFIRM and SENTINEL), natalizumab was
approved by the US Food and Drug Association in 2004 for relapsing-remitting multiple scle-
rosis. However, in 2005, it was taken off the market because three patients developed progres-
sive multifocal leucoencephalopathy, two with multiple sclerosis and one with Crohn’s disease.
Further use, including European Union approval, followed in 2006, with restricted distribution
focussed on safety. The status of John Cunningham virus (JC virus) is checked and monitored in
treated patients, who are then repeatedly consented for treatment with natalizumab.

Progressive multifocal leucoencephalopathy is due to activation of the polyomavirus.

Infection with the JC virus is usually asymptomatic in immunocompetent individuals. How-
ever, latent infection means that it can reactivate under appropriate conditions. Other dis-
ease-modifying drugs for multiple sclerosis have been implicated in progressive multifocal
leucoencephalopathy, but the risk with natalizumab has been more frequent.
Alemtuzumab
Alemtuzumab, initially called Campath 1H (to reflect Cambridge pathology) is a monoclo-
nal antibody against CD52, which depletes B cells. Hermann Waldmann at the University
of Cambridge had suggested that the Cambridge academic neurology team consider using
this drug in multiple sclerosis. It had already gained a license in 1991 for childhood chronic
lymphocytic lymphoma. Alemtuzumab had a chequered path to licensing for treatment of
relapsing-remitting multiple sclerosis. Multiple drug companies, regulations, large invest-
ments of time and money as well as individual interventions eventually yielded the MS
CARE 1, 2 and extension studies, revealing an effective licensed product, albeit with rec-
ognised adverse effects (Grave’s disease 30%, idiopathic thrombocytopenic purpura 1–3%,
Goodpasture’s syndrome 0.1%). Intriguingly, a lymphocyte-depleting drug is associated with
autoimmune adverse effects. Alemtuzumab was launched in 2013 and recommended by
NICE for its full indication in May 2014.
This annual treatment for two years (infusion ×5 days in year 1 and infusion ×3 days in
year 2) became well established as one of the more effective disease-modifying treatments for
multiple sclerosis. Like some other drugs (natalizumab and fingolimod), alemtuzumab also
had demonstrated sustained disability improvement, although the mechanism for this has
not been clearly elucidated. In the studies (MS CARE 1, 2 and extension studies), early treat-
ment was initiated, hinting at the need for prompt initiation for maximum benefit. However,
in 2019, a safety alert was raised. The European Medicines Agency reported rare serious disor-
ders within one to three days of the alemtuzumab infusion, including myocardial infarction,
intracerebral haemorrhage, cervical arterial dissection, pulmonary alveolar h aemorrhage
and thrombocytopenia. Delayed autoimmune complications were also a concern, including
autoimmune hepatitis, haemophilia A, idiopathic thrombocytopenic purpura, thyroid dis-
orders and rarely, nephropathies or haemophagocytic lymphohistiocytosis. There was also
increased risk of serious infections and reactivation of Epstein–Barr virus. Restricted used of
alemtuzumab ensued.
References
1. Lublin FD, Reingold SC, Cohen JA et al. Defining the clinical course of multiple sclerosis.
Neurology 2014;83(3):278–86.
2. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity
of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol.
2000;47(6):707–17.
3. Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 revisions of the
McDonald criteria. Lancet Neurol. 2018;17(2):162–73.
4. Institute of Medicine. Improving Diagnosis in Health Care. Washington, DC: National Academies
of Sciences, Engineering, and Medicine, 2015 (http://iom.nationalacadmies.org/Reports/2015/
Improving-Diagnosis-in-Healthcare.aspx), page 2.

Learning Points
• Multiple sclerosis is a common cause of neurological disability, which shows latitudinal variation
in incidence.
• Since 1995, an increasing number of disease-modifying drugs have emerged that reduce the
relapse rate of patients with relapsing-remitting multiple sclerosis. Different blood-monitoring
strategies are required for disease-modifying drugs.
• Individuals with multiple sclerosis are at increased risk of epilepsy.
• The ultimate goal of a disease-modifying drug in multiple sclerosis is NEDA.
• Risks of complications from disease-modifying therapy have emerged from phase 4 or post-
marketing surveillance data from larger numbers of patients.
1. What was the impact of the condition on you?
Loss of feeling in my right hand, my right leg was a dead weight and my left leg gave way. I had poor
balance and poor co-ordination. I had memory loss, I could not retain information. I could not
control my bladder and bowels, in that at times I did not get a warning.
Depression and anxiety due to constant fatigue, frustration, confusion, loss of vision from my left eye,
and later diagnosed with epilepsy.
Social meetings were minimal. Family events were not attended due to my poor walking ability.
2. What can or could you not do because of the condition?
I had difficulty remembering or planning things, writing or signing, holding my bladder and control
of bowel movements. I could not walk very well and I could not concentrate. Now my memory and
concentration have improved.
I dropped out of college due to depression, fatigue, lack of memory and poor concentration.
Carrying the weight of my right leg and numbness in my right hand was most frustrating. My bladder
and bowel problems caused me to fear of going out. Optic neuritis and seizures were by far the scariest
experience!
Overcoming obstacles. Exercise slightly helped my mobility. Reminders helped my memory. I learned
to write and do tasks with my left hand. The OT [occupational therapist] helped my balance and
movement a lot. The monthly infusions have helped a lot, especially with the fatigue.
6. What do you hope for in the future for your condition?
In the future, I hope that patients with MS [multiple sclerosis] do not lose hope. I hope they know to
help themselves alongside the treatment. Lifestyle changes worked for me. I hope that one day there
will be a cure.

5 Chasing Periorbital Nerves
CASE
History
A 65-year-old man developed a swelling of his left medial canthus. He was referred from out-
patient Ear, Nose and Throat to Ophthalmology. However, prior to an Ophthalmology assess-
ment, he developed horizontal diplopia. A neurologist confirmed a left VI cranial nerve palsy.
He had visual acuity of 6/6 bilaterally. A non-contrast MRI scan of the brain was reported as
normal. The diplopia resolved within two months, as confirmed by an ophthalmologist and
a neurologist.
He was a non-smoker and drank one or two glasses of wine per day. His mother had a
melanoma at the age of 70 years.
Five months after the onset of diplopia, the medial canthus lesion was excised; it was noted
that the lesion was adherent to underlying bone. Clinically, there was a patch of numbness in
the distribution of the left inferotrochlear nerve (a branch of the nasociliary nerve supplying
medial upper and lower eyelids, lateral part of nose above the medial canthus and medial con-
junctiva). Histology showed a squamous cell carcinoma with immunohistochemistry stain-
ing for cytokeratin 5/6 and epithelial membrane antigen (Figure 5.1). Further clearance was
performed but identified no further evidence of tumour.
Seven months later, a mild left-sided headache developed. Double vision recurred. He was
neurologically re-assessed.
Examination
He had a fair skin complexion. Visual acuity was 6/6 and there was a normal pupillary light
reaction. There was left proptosis and failure of left eye abduction and impaired left eye
upgaze. There was no optic nerve head swelling and no other neurological deficit. He was
re-investigated.
Investigations
An MRI of the brain and orbits with contrast revealed a left intraorbital abnormality, suspi-
cious for malignant infiltration (Figure).
A further left orbital biopsy was performed, confirming a poorly differentiated squamous
cell carcinoma (strong staining with cytokeratin 5/6 and epithelial membrane antigen).
29

Figure 5.1 (A) Histology of the canthal tissue biopsy shows granulation tissue that is infiltrated by pleomorphic
squamoid cells exhibiting dense eosinophilic cytoplasm, intercellular bridges and some keratinisation is seen
focally. These atypical cells form nests and large groups with irregular contours as well as trabeculae and single cell
forms. (B) Focally, sarcomatoid morphology with elongated spindle cell-like appearances and conspicuous mitotic
figures are seen. There are also entrapped skeletal muscle bundles. (C) Cytokeratin 5/6 immunohistochemistry
confirms the squamous phenotype of the lesional cells and highlights the tumour silhouette. (D) Epithelial
membrane antigen immunohistochemistry shows patchy focal positivity that is consistent with squamous cell
carcinoma.
Figure 5.2 (A) Coronal and (B) axial fat suppressed T1 MRI of the orbit with contrast showing thickened and
enhancing soft tissue with central necrosis in the superomedial left orbit.

Chasing Periorbital Nerves 31
Diagnosis: Superior Orbital Fissure Syndrome or

Rochon-Duvigneaud Syndrome (from Perineural
Infiltration of Squamous Cell Carcinoma of the Orbit)
Management
A specialist multidisciplinary management plan was developed. The patient underwent a left
orbital exenteration with clear margins followed by radiotherapy (66 Gray in 33 fractions) in
order to reduce the risk of relapse. He developed a naso-orbital fistula. The weeping discharge
severely restricted outdoor and social activities as frequent dressings were required. A pros-
thesis was fitted. The fistula was subsequently treated with three osseo-integrated implants.
However, the fistula persisted with ongoing discharge. A paramedian forehead flap hampered
the fitting of the prosthesis.
Comment
Differential Diagnosis of VI Cranial Nerve Palsy
The VI cranial nerve emerges anteriorly at the pontomedullary junction and then ascends in
front of the brainstem. It makes a sharp angle over the tip of the petrous bone into Dorello’s
canal (under the petroclinoid ligament) before entering the back of the cavernous sinus. It
next enters the orbit through the superior orbital fissure to pass laterally to the lateral rectus
muscle.
Six syndromes of the VI cranial nerve (abducens) are recognised, defined by the anatomi-
cal location of the nerve injury (Figure 5.3), which can provide clinical clues.
1 Brainstem syndrome – The VI cranial nerve nucleus supplies the lateral rectus muscle
and abducens internuclear neurones, which project via the medial longitudinal
fasciculus to the contralateral oculomotor nerve for medial rectus innervation. A
nuclear VI cranial nerve palsy therefore causes ipsilateral conjugate horizontal gaze
palsy. Involvement of other pontine structures may cause Millard–Gubler syndrome (VI
cranial nerve palsy, ipsilateral VII cranial nerve palsy and contralateral hemiparesis),
Raymond’s syndrome (VI cranial nerve palsy and contralateral hemiparesis) and
Foville’s syndrome (horizontal conjugate gaze palsy due to ipsilateral VI cranial nerve
palsy and involvement of the parapontine reticular formation, ipsilateral V, VII and VIII
cranial nerve palsies with ipsilateral Horner syndrome).
2 Subarachnoid space (prepontine cistern) syndrome– Downward displacement of the
brainstem may displace the VI cranial nerve. This is the explanation for a VI cranial
nerve lesion in patients with idiopathic intracranial hypertension; one third of patients
with idiopathic intracranial hypertension have a VI cranial nerve lesion.
3 Petrous apex syndrome – The VI cranial nerve can be damaged at the tip of the petrous
pyramid in Dorello’s canal. Gradenigo syndrome (as can occur with infection of the
petrous temporal bone from otitis media) consists of VI cranial nerve palsy, ipsilateral
decreased hearing, ipsilateral facial pain from V cranial nerve involvement and
ipsilateral facial weakness.

Superior orbital fisuure
Cavernous sinus
Petrous temporal bone

Petroclinoid ligament and Dorello’s canal
Prepontine cistern/subarachnoid space

Abducens nerve
Corticospinal tract
Facial nerve
Brainstem (nuclear and fascicular)
Figure 5.3 Schematic diagram of the course of the left VI cranial nerve and potential sites of injury.
4 Cavernous sinus syndrome – Lesions in the cavernous sinus cause VI cranial nerve palsy
in association with III, IV and Va–b cranial nerve lesions, Horner syndrome, optic nerve
or optic chiasm lesion and pituitary involvement.
5 Orbital apex syndrome-visual loss (optic nerve involved)/superior orbital fissure
syndrome-vision spared (optic nerve not involved) – Early proptosis can suggest an
orbital cause for VI cranial nerve lesion. It is difficult to distinguish between III, IV and
VI cranial nerve palsies and mechanical restriction of the globe. Cranial nerve Va is also
affected.
6 Isolated VI cranial nerve palsy – This syndrome has none of the signs in the other
VI cranial nerve syndromes. Isolated VI cranial nerve palsy is usually an ischaemic
mononeuropathy in adults. This was the presumed aetiology in our patient’s initial
presentation, particularly because of the recovery. Presumed microvascular VI cranial
nerve palsy may mimic early perineural cutaneous squamous cell carcinoma invasion [1].
Cutaneous Periorbital Squamous Cell Carcinoma

Malignant tumour spread can occur via direct invasion, or by lymphatic and vascular routes,
but perineural spread can also occur via layers of the perineurium and the endoneurial com-
partment guided by neurotrophins, growth factors and axonal guidance receptors dependent
on the expression of neural cell adhesion molecules.

Chasing Periorbital Nerves 33
Squamous cell carcinoma accounts for 5–10% of periocular tumours. Increasing age,
prolonged sun exposure, male sex, fair complexion, some skin disorders (e.g. albinism)
and immunosuppression (particularly for renal transplant) all increase the risk of cutane-
ous squamous cell carcinoma. Between 2 and 6% of patients with cutaneous basal and squa-
mous cell carcinomas have evidence of perineural invasion [2]. Mid-face location, male sex,
high histological grade and increasing tumour size are risk factors for perineural invasion.
Cranial nerves V and VII are most commonly involved due to their extensive subcutaneous
distribution.
Management of Periocular Cutaneous Squamous Cell Carcinoma

Management of periocular cutaneous squamous cell carcinoma is challenging, requiring a
specialist oculo-facial plastic surgeon to co-ordinate interdisciplinary management, surgical
reconstruction and post-operative surveillance.
Delay in Diagnosis
A delayed, missed or incorrect diagnosis is defined as a misdiagnosis. Cognitive or heuris-
tic errors (faulty clinical reasoning) [3], system-related errors and an incorrect interpre-
tation of diagnostic tests constitute the important domains or themes underlying many
misdiagnoses.
Should perineural invasion have been suspected when this patient initially presented with
VI cranial nerve palsy? The resolved lateral rectus weakness with initial normal neuroimag-
ing (albeit without contrast) pointed towards the initial VI cranial nerve palsy being due to
microvascular ischaemic disease. The medial canthus lesion was not biopsied at that stage. A
partial resolution of a VI cranial nerve palsy has been reported in periorbital squamous cell
carcinoma [1], but a spontaneous and full resolution of a VI cranial nerve would be unusual
in the presence of a tumour.
Nomenclature and Definitions

There are a number of terms used to describe the anatomical location of pathological pro-
cesses affecting cranial nerves in and around the orbit.
The orbital apex syndrome involves the optic nerve, the oculomotor nerve, the trochlear
nerve, the abducens nerve and the ophthalmic division of the trigeminal nerve. Clinically,
there is loss of vision plus painful and limited eye movements. The term orbital apex syn-
drome is now reserved for such patients with loss of vision. There may also be proptosis,
altered corneal reflex, a relative afferent pupillary defect, optic disc oedema or atrophy and
choroidal folds.
The superior orbital fissure syndrome (also known as Rochon-Duvigneaud syndrome)
is caused by lesions anterior to the orbital apex and in close proximity to the annulus of Zinn
(ring of fibrous tissue that is the common origin for four rectus muscles and surrounds the
optic nerve). There is impaired function of cranial nerves III, IV, Va and VI. As in our patient,
the optic nerve is generally spared.
The cavernous sinus syndrome and the superior orbital fissure contain the same struc-
tures, making it clinically difficult to state whether a lesion is in the cavernous sinus or the
superior orbital fissure. The maxillary division of the trigeminal nerve may occasionally be
involved in the cavernous sinus syndrome but not in the superior orbital fissure syndrome.
Sympathetic carotid plexus involvement also occurs in the cavernous sinus syndrome.

Another random document with
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majority of the colonists were men whose word was unworthy of
credit, but had Columbus been a just and able ruler, surely some one
outside of his own family would have spoken favorably of him. We
need not suppose that he was responsible for the chills and fever
which harassed the colonists, or that he originated all the hurricanes
and earthquakes that visited the island; but there is sufficient reason
to believe that he was not well fitted to win the obedience or respect
of the colonists, and in the circumstances we may restrain our
indignation at the appointment of the investigating commissioner.
Ferdinand and Isabella evidently had confidence in the judgment
and integrity of Bobadilla, for they gave him three or four different
commissions, with authority to use any or all of them, as he might
see fit. As the event proved, he was unworthy of this confidence; but
it would not be fair to accuse the monarchs of deliberate cruelty
because they overrated their commissioner’s intelligence.
Bobadilla arrived at San Domingo just after the suppression of
Mexica’s rebellion, and while Columbus was still absent at Fort
Concepcion. As he entered the river he saw two gibbets decorated
with rebel corpses, and the sight was not adapted to remove the
impression, which he undoubtedly had, that Columbus was cruel and
tyrannical.
His first act was to publish a proclamation that he had come to
redress grievances, and that every one in San Domingo who had
any cause of complaint against Columbus or his brothers should at
once speak out, or ever after hold his peace. The entire population,
with the solitary exception of those who were locked up in jail, at
once hastened to Bobadilla and told their grievances.
The commissioner, appalled at the flood of accusation which he
had set loose, strengthened his mind by attending mass, and then
caused his commission appointing him to inquire into the late
rebellion to be read. This having been done, he demanded that Don
Diego Columbus, who was in command of San Domingo, should
surrender to him Guevara and the other rebel prisoners. Don Diego
said that he held the prisoners subject to the Admiral’s order, and
must therefore decline to surrender them. Bobadilla next produced a
second commission appointing him Governor of the New World, and
remarked that perhaps Don Diego would now condescend to give up
the prisoners. Don Diego conceded that the commission was a very
pretty one, especially in point of seals and ribands, but maintained
that his brother had a better one, and that, on the whole, he must
decline to recognize Bobadilla as Governor. Exasperated by this
obstinacy, Bobadilla now produced a third commission, ordering the
Admiral and his brothers to surrender all the forts, public buildings,
and public property to him, and forcibly argued that since Guevara
was in a fort, the surrender of the fort would include the surrender of
Guevara, in accordance with the axiom that the greater includes the
less. Don Diego calmly insisted that this was not a case in which
mathematics were concerned, and that he proposed to obey the
Admiral’s orders, no matter if Bobadilla should keep on producing
new commissions at the rate of sixty a minute for the rest of his
natural life.
Bobadilla, finding that Don Diego’s obstinacy was proof against
everything, went to the fort and called on the commander to give up
his prisoners, and when the commander refused, broke into the fort,
at the head of the delighted colonists, and seized on Guevara and
his rebel companions. He then took possession of all the property
and private papers belonging to the Admiral, and, moving into his
house, proceeded to assume the duties of Governor and
investigator.
Columbus, when he heard of these proceedings, was somewhat
astonished, and remarked to his friends that he feared this Bobadilla
was a little rash and impolitic. He wrote to him, welcoming him to the
island, and suggesting that it would be well if he were to draw it mild
—or words to that effect. In reply, Bobadilla sent him an order to
appear before him at once, and enclosed a letter from the
sovereigns, ordering Columbus to obey the combined Governor and
Commissioner in all things. Being wholly without means of
resistance, Columbus perceived that magnanimity was what
posterity would expect of him, and therefore immediately went to
San Domingo and presented himself before Bobadilla.
[Æt. 64; 1500]
That amiable and delicate person received the Admiral as if he
were an Italian brigand for whom a reward of $25,000 had been
offered, and ordered him and his brother, Don Diego, to be put in
irons. As a striking instance of the irony of fate, it may be mentioned
that the man who placed the irons on Columbus was his former
cook, whose self-respect had often been wounded when his master
complained that the maccaroni was burned or that the roast pork
was insufficiently cooked. Now the cook had his revenge, and we
can imagine with what zest he remarked, after the fetters were
riveted, that he hoped that for once the Admiral would admit that the
job was well done, and would notice the rare pleasure with which his
ex-cook had performed it, whatever might have been that humble but
honest individual’s previous sins in respect to pork and maccaroni.
Undoubtedly he said something of the kind, for a man who could put
chains on Columbus was surely bad enough to make puns without
shame or remorse. At the command of Bobadilla, Columbus wrote to
Don Bartholomew, who was in Xaragua, inviting him to come and
share the fetters of his illustrious brother and the well-meaning Don
Diego—which the Adelentado accordingly did.
Having the entire Columbus family thus safely in his power,
Bobadilla proceeded to take testimony against them, with all the
enthusiasm of a partisan Senate committee preparing material for a
Presidential campaign. There was no lack of testimony. The colonists
made affidavits with a wealth of imagination and fervency of zeal
which a professional detective employed to furnish evidence in an
Indiana divorce case might emulate but could not surpass.
Columbus was accused of nearly all modern and ancient crimes,
from stealing pearls and gold-dust up to the crowning infamy of
requiring Spanish gentlemen to work. It was conclusively shown that
he was the worst man then living, with the possible exception of the
Adelentado, and that Guevara and the other rebels were patent,
direct-acting saints, who deserved every possible honor. Having
made up an effective campaign document from this mass of brilliant
testimony, Bobadilla sent it, together with Columbus and his two
brothers, to Spain.
Don Alonzo de Villejo, who commanded the vessel on board of
which was the fallen Admiral, was a gallant sailor, and, as soon as
the ship was safely out of the harbor, said, in the strongest seafaring
language, that he would consent to the immediate condemnation of
his personal eyes if the Admiral should wear those doubly
condemned chains another moment. But Columbus courteously and
firmly refused to be liberated. He said the chains had been put on
him by order of the King and Queen, and that the King and Queen
would have to take them off, or he would wear them to his dying day,
and serve them right. This was a stout-hearted resolution, but,
perhaps just to gratify Villejo, Columbus consented now and then to
slip one wrist out of his fetters, which he must have found very
inconvenient when he was engaged in writing letters.
The voyage was uneventful, and in the early part of October the
ship reached Cadiz and Columbus was delivered to the local
authorities. The moment it was known that he had been brought
home in irons he became immensely popular, as indeed the man
who made so unexpected and brilliant a sensation deserved to be.
Everybody said it was an outrage, and that Bobadilla was clearly the
beast spoken of in the Apocalypse.
Columbus did not venture to write to the Queen, but he wrote a
long and eloquent account of his bad treatment to one of the ladies
of the court, who he knew would instantly read it to Isabella. That
estimable sovereign was greatly shocked, and Ferdinand felt that, as
a prudent husband, he must share his wife’s indignation. The royal
pair immediately wrote a letter expressing the warmest sympathy for
Columbus, inviting him to court, and enclosing a check for nearly
$8500 to pay his travelling expenses and enable him to buy a few
clean collars and other necessaries.
[Æt. 64–66; 1500–2]
The Admiral, taking off his chains and putting them in his trunk
as souvenirs of royal favor, went to Granada, where the court was
then held, and being admitted to the royal presence fell at the feet of
Isabella, which he appears to have carefully distinguished from
Ferdinand’s feet, and burst into tears. The monarchs personally
raised him up, in spite of his weight, and Isabella told him it was a
perfect shame, and that Bobadilla’s conduct was quite too awfully
horrid. Ferdinand behaved very properly, and agreed with Isabella
that all the rights and honors of Columbus should be restored to him,
and that he could feel perfectly easy as to the future. Bobadilla’s
elaborate campaign document was tossed aside with as little
attention as if it had been a Patent Office Report, and his attempt to
fire the royal Spanish heart was a complete failure.
Columbus now expected that he would be directed to return
immediately to San Domingo, and to send Bobadilla home in
disgrace; but the monarchs delayed to issue the desired orders.
Ferdinand had evidently made up his mind to do nothing of the sort.
He considered himself a deeply injured king. In the confident
expectation that Columbus would be drowned, he had consented to
grant him unprecedented honors and privileges, in the improbable
contingency of the discovery of a new road to Asia or a new
continent. Columbus had meanly taken advantage of this to discover
a continent and innumerable islands, and had, as Ferdinand felt,
cheated him out of a splendid title and a handsome revenue. Now
that Columbus had temporarily lost these ill-gotten advantages,
Ferdinand did not think it necessary to restore them. He therefore
informed the Admiral that it would be best for him to remain in Spain
for, say, ten years, until things could be made pleasant for him in
Hispaniola. In the mean time Don Nicholas de Ovando would be sent
out to supersede Bobadilla and to ascertain what damages
Columbus and his brothers had sustained, so that full payment could
be made. He assured the Admiral that everything should be
arranged to his satisfaction, and that he should lose nothing by
remaining in Spain.
[Æt. 64–66; 1500–2]
There is no reason to suppose that Columbus was deceived by

the King’s attenuated explanation, but he could not well find fault
with it. De Ovando sailed for San Domingo with a fleet of thirty
vessels and twenty-five hundred men. Columbus took lodgings in
Granada, and to employ his time resolved to attend to the little
matter of recovering the Holy Sepulchre, a duty which he had long
neglected and had recently bequeathed to his son. He drew up a
long memorial, urging the King and Queen to organize a new
crusade for the capture of Jerusalem. He demonstrated to his own
satisfaction that he had been born in order to discover a new world
and to redeem the Holy Sepulchre. He had fulfilled the first of these
duties, and was now ready for the second. All that he required was
an army and a sufficient supply of money.
Ferdinand did not embrace the suggestion with much
enthusiasm. He said he would see about it, and hinted that as
crusading was an expensive business, it might be well to ascertain
whether the Sultan would be willing to look at the matter from a
business point of view and make some arrangement in regard to the
Holy Sepulchre which would settle the matter in an amicable and
inexpensive way.
[Æt. 64–66; 1502]
The crusading scheme being a failure, the Admiral devised a

new plan of exploration. He wrote another memorial, setting forth the
advantages of discovering the Panama Canal. He admitted that
either China had been moved, or else it lay farther west of Spain
than he had at first supposed. At any rate, it had become clear to his
mind that there was a continent which blocked up the direct route to
China, and that the only way to get through this obstacle was to
discover a canal à niveau, cutting the Isthmus of Panama. He had
not the least doubt that the canal was there, and that he could find it
with perfect ease were he to be supplied with ships and men, and
were a proper reward to be offered for its discovery. Now that he had
time for reflection, he was inclined to think the market had latterly
been overstocked with new countries—a result which he had feared
when the sovereigns so injudiciously—if he might be allowed the
expression—gave to everybody the privilege of exploration. In regard
to the Panama Canal, however, he was confident that it would meet
a great public want, and that its discovery would be warmly
applauded by everybody, with the possible exception of the
inhabitants of Bohemia, who, although they had no commerce, might
insist that the canal should not be discovered unless the discoverer
would agree to present it to them.
The plan pleased Ferdinand and Isabella. A fleet of four ships
was ordered to be made ready, and Columbus was authorized to
take with him his brother Don Bartholomew and his personal son,
Diego. The monarchs also wrote Columbus a letter, in which they
said many pleasant and inexpensive things, and promised him the
restoration of all his rights. He was now so enfeebled by age and
hardship that it seemed safe to promise him anything, provided the
promises were not to be fulfilled until after his return from his
intended voyage.
CHAPTER XVII.
HIS FOURTH EXPEDITION.
[Æt. 66; 1502]
ON the 9th of May, 1502, Columbus once more sailed from

Cadiz. The passage across the Atlantic was in no way remarkable.
The fleet touched as usual at the Canaries, and on the 15th of June
arrived at one of the smaller Caribbean islands. Columbus had been
strictly forbidden to touch at San Domingo, because it was feared
that he would get into trouble with the local authorities, and would
then come back to Spain to defend himself against false
accusations. However, as one of his ships was unseaworthy, he
convinced himself that it was a matter of necessity and mercy for him
to go to San Domingo and obtain a better vessel.
He arrived in due time at the forbidden port, but Ovando refused
to permit him to land, and ordered him to put to sea immediately.
Columbus then informed Ovando that a hurricane was approaching,
and begged permission to lie at anchor in the shelter of the harbor
until fair weather should appear; but his petition was refused.
Ovando said there was not the least sign of an approaching
hurricane, and that he was a bird far too advanced in years to be
caught by the Admiral’s meteorological chaff.
There was at the time a large fleet of vessels lying in the harbor,
and on the point of sailing for Spain. On board of the fleet were
Roldan, Bobadilla, many discontented colonists, and a large quantity
of gold. Now Columbus, who was learned in weather, was in earnest
when he prophesied a hurricane, and he felt sad in view of the
danger which threatened the gold on board the fleet in case the
ships should put to sea before the hurricane arrived. He warned
Ovando not to let the fleet depart, but Ovando and everybody else
laughed to scorn “Old Italian Probabilities,” and mocked at his areas
of barometrical depression and approaching storm-centres.
Columbus sailed away and sought shelter under the lee of the
island, and the fleet with Bobadilla and the gold put to sea. Two days
later a hurricane that the New York Herald would have been proud to
launch against the shores of Great Britain wrecked the fleet,
drowned Bobadilla and Roldan, and sunk the gold to the bottom of
the sea. A few vessels managed to work their way back to San
Domingo, but only one reached Spain. The fortunate vessel had on
board a quantity of gold belonging to Columbus, and in his opinion
this fact was all that saved her.
The Admiral’s vessels rode out the storm safely, though they
were much damaged, and, after it was over, put into Port Hermoso to
refit. Having patched up the vessels, Columbus set sail for the
Panama Canal, and after a voyage of about six weeks he reached a
group of small islands on the coast of Honduras. Here he met a large
canoe filled with the ablest natives he had yet seen. They had
hatchets and other tools made of copper, and were dressed in cotton
garments woven by themselves. They were probably from Yucatan,
for they claimed to belong to a civilized country situated farther west
and possessing magnificent cities. The Admiral said he was not
looking for cities as much as he had been, that he was on his way to
India, and that he had no time to go to Yucatan. Thus he lost the
chance of discovering the curious and fantastic Maya and Aztec
civilization which Cortez afterward found and destroyed.
There was little in the early part of the Admiral’s voyage along
the Central American coast which deserves especial notice. He
coasted Honduras and Costa Rica, finding an oppressive sameness
of savages and bad weather. The savages were peaceful, but the
weather was not. It rarely condescended to indulge in anything less
violent than a hurricane, and always blew from precisely the direction
in which the Spaniards wished to steer. The Costa Rican savages
told Columbus that the Ganges was a few days’ journey farther west,
and that vessels carrying cannons frequently came to the large city
of Ciguari, which was still nearer than the Ganges.
[Æt. 66; 1503]
This was, on the whole, the most able and satisfactory aboriginal
lie which had yet been told to Columbus, and it made him confident
that he would arrive in India in a few days. Lest the savages should
receive too much credit for inventive genius, it should be mentioned
that they must have been greatly assisted by leading questions put
by the Spaniards, otherwise they could not have hit upon the name
of the Ganges. The mention of the ships armed with cannon which
came to the mythical city of Ciguari was, however, a master-stroke
for which the natives are entitled to full credit. Travellers who have
visited Central America in our day would perhaps find it easier to
understand the habits and customs of the people, were it generally
known that their remote Indian ancestors were likewise men of
brilliant imagination and utter fearlessness of assertion.
Leaving these mendacious but encouraging savages, Columbus
came to Veragua, a country lying farther south and really abounding
in gold. But now that he had finally reached a place where gold was
abundant, the precious metal for which Columbus had searched so
long and eagerly seemed to have lost its charm. He was too anxious
to reach the Ganges to be willing to stop for anything; so, after laying
in a few gold plates, he stood on his southward course.
The ships and the Admiral were by this time greatly in want of
repairs. Columbus was suffering from gout, fever, and old age, while
the ships, in addition to the latter complaint, were leaky and covered
with barnacles. The crews began to grumble loudly, and on the 5th of
December, Columbus having failed to find the Ganges, the city of
Ciguari, or the Panama Ship-Canal, thought it best to yield to the
force of public opinion before it should express itself with handspikes
and knives. He therefore consented to abandon his search and turn
back to Veragua, where he hoped to be able to collect enough gold
to convince Ferdinand and Isabella of his wisdom in postponing his
intended geographical discoveries.
No sooner had the ships turned and stood to the northward, than
the wind, with a vicious display of ill-temper, shifted and became
once more a head-wind. It blew if anything harder from its new
quarter than it had blown before, and it was not until early in January
that the fleet reached Veragua and anchored in the river Belen.
[Æt. 67; 1503]
The sailors were glad to go ashore; for, though there was

nothing to drink, there was gold to be got, and while on shore they
were rid of the task of sailing clumsy and leaking ships. The Admiral,
in his feeble health, was greatly in need of rest, and he was not
aware that he had found precisely the worst locality in the Western
Hemisphere for fever and mosquitoes. The Adelentado was sent
with a large force to explore the surrounding country, from which he
returned with the report that the natives had a great deal of gold in
their possession. Of course the Spanish soldiers merely looked at
this gold, and complimented the natives on their possession of so
valuable an article; we need not suppose they were so wicked as to
steal it, and thus convert the friendly Costa Ricans into enemies.
Being satisfied with the Adelentado’s report, Columbus decided
to leave most of his men to found a colony on the banks of the
Belen, while he should return to Spain for supplies.
The natives had hitherto been peaceable; but when they saw the
Spaniards building houses on their land, they felt that it was time to
take proceedings for dispossession. Columbus received information
that the local cacique, Quibian, was collecting an army to attack the
colony, and he sent Diego Mendez to investigate the matter.
Quibian’s village was on the river Veragua, not far from the
Belen, and Mendez soon found his way thither. He was told that the
cacique was confined to his house with a wounded leg. Mendez
immediately said that he was a doctor, and would repair the leg; but
Quibian’s son said, Oh no, he rather thought Mendez would not
repair that particular leg just then. As the savage followed up this
remark by hitting Mendez over the head, the latter admitted that
perhaps he was mistaken, and hurriedly remembered that he had an
engagement which would require his immediate return to the colony.
There was now no doubt that Quibian intended to fight, and the
Adelentado, remarking that a cacique in the hand was better than
several in the bush, proposed to go in person and capture Quibian.
Taking seventy-four men with him, Don Bartholomew managed to
obtain an interview with the cacique, whom he instantly seized and
bound. The natives offered no resistance, and the Adelentado,
gathering up the wives and children of Quibian, prepared to return.
The cacique was laid in the bottom of a boat, and pretended to
suffer so much pain that the officer in charge of the boat loosened
his bonds. Quibian thereupon jumped overboard and, as it was now
night, escaped safely to land; while the Spaniards believed that he
had been drowned.
The danger of an attack by the savages being thus, in the
opinion of the Admiral, at an end, he prepared to depart for Spain.
The water on the bar at the mouth of the river was so low that the
ships could not pass over it without being lightened. Their stores
were therefore disembarked, and after getting into deep water the
ships were anchored and the stores were brought back to them in
boats.
When the fleet was nearly ready to sail, Columbus sent Diego
Tristan and eleven men ashore to obtain water. As they neared the
settlement, they saw a horde of savages rush out of the jungle and
attack the colonists. The savages were led by Quibian, who, being a
heathen and a barbarian, imagined that he had more right to his
wives and children than the Spaniards had. Tristan was an excellent
old sailor, who held that it was the first duty of man to obey orders.
He had been sent for water and not for blood, and accordingly he
never thought of interfering in the fight, but rowed steadily up the
river in search of fresh water. The Spaniards fought bravely, and
repulsed the attack of the natives; but the latter, instead of
appreciating Tristan’s fidelity to duty, fell upon him and killed him and
his whole party, with the exception of one man, who fled to the
settlement with his sanguinary story.
The Spaniards were now convinced that they had no more use
for Central America, and rushed to the ship that lay in the river,
determined to return to Spain with the Admiral. The ship, however,
could not be got over the bar, and the terrified colonists consented to
listen to the Adelentado’s advice, and to attempt to fortify the
settlement. They went on shore again, and threw up barricades—
which, as every one knows who is familiar with French politics,
consist of boxes, paving-stones, omnibuses, news-stands, and other
heterogeneous articles piled together.
The barricades were better than nothing as defensive works, but
they were miserably weak. Eleven Spaniards had been killed and
several more wounded, including Don Bartholomew, and as the
savages vastly outnumbered them, the prospect that any of the
colonists would escape was extremely small.
Columbus could not understand why Tristan did not return. He
knew that Tristan was a faithful and obedient man, and that there
was no rum to be had at the settlement, so that he finally began to
fear that the natives had been acting in a disorderly way. This fear
was increased by the conduct of Quibian’s wives and children, who
were on board one of the vessels. During the night after Tristan’s
departure these hasty and ill-bred prisoners began to commit suicide
by hanging themselves or by jumping overboard, and continued this
recreation so persistently that by morning not one of them was left. If
women and children could do such an uncivil thing as this, it was
only too probable that the men of the same race were capable of
creating riot and bloodshed ashore.
There was only one available small boat at the command of the
Admiral, and the sea on the bar was so heavy when the
disappearance of the Quibian family was discovered that Columbus
did not dare to send the boat ashore. Fortunately, one of the pilots,
Pedro Ledesma, offered to swim ashore if the boat would carry him
part of the way. His offer was of course accepted, and when the boat
was a short distance from the shore Ledesma sprang overboard and
successfully swam through the boiling surf. He returned in a short
time, bringing the news that the colonists were in immediate danger
of being massacred.
Unless the sea should go down, Columbus could give no
assistance to the men on shore, and there was no prospect that the
sea would go down.
Most men in the position of the Admiral would have been at a
loss what to do, but Columbus was a man of uncommon resources.
He promptly had a vision. A voice spoke to him in the best Scriptural
style, and assured him that everything was all right; that the colonists
would be saved, and that no one need feel any uneasiness. It is
probable that this was the voice of a sainted and remote ancestor of
the late William H. Seward, and it filled the Admiral with confidence
—which confidence it is possible was shared by the sailors when the
story of the vision was told to them. The voice proved to be a
veracious one, for the next morning there was a dead calm, and the
colonists, with all their portable property, were safely rafted on board
the ships, which immediately set sail for San Domingo in order to
refit.
It was now the end of April, but the weather declined to improve.
Probably Columbus, like a skilful commander, made his men draw
lots with a view to pilgrimages, and encouraged them to vow to
attend church in their shirts; but there is no mention of these
manœuvres in the Admiral’s log. The ships were nearly eaten up by
the teredo and could with difficulty be kept afloat. One was
abandoned, and the crew taken on board the other two. These
reached the islands lying south of Cuba which Columbus had
discovered on his second voyage, where they were detained nearly
a week by violent storms. When the voyage was resumed the head-
winds promptly resumed also, and finally, with his ships leaking like
sieves out of repair, and his provisions nearly exhausted, Columbus
bore up for Jamaica, which he reached on the 23d of June. The next
day he entered the harbor of Port Santa Gloria, where his decrepit
vessels were run ashore to keep them from sinking, and were firmly
lashed together.
CHAPTER XVIII.
HIS LAST YEARS.
[Æt. 67; 1503]
THE ships were now hopeless wrecks, and there was nothing
more to be done with them except to abandon them to the
underwriters and claim a total loss. The only chance that the
Spaniards could avoid laying their bones in the bake-ovens of the
Jamaican natives was in communicating with San Domingo, but in
the absence of any efficient postal service this chance seemed very
small. Diego Mendez, who was the captain of one of the vessels,
and who had earned the confidence of Columbus by the skill with
which he superintended the escape of the beleaguered colonists
from Quibian’s hordes, volunteered to take a canoe and, with the
help of Indian paddlers, make his way across the one hundred and
twenty miles of sea which stretched between Jamaica and
Hispaniola. He started on his voyage, and skirted the shore of
Jamaica, so that he could land from time to time and take in
provisions.
It struck the natives that they might as well improve the
opportunity to lay in provisions for themselves, and accordingly they
attacked Mendez with great energy and appetite, and made him and
his Indian paddlers prisoners. There being in all seven prisoners, a
dispute arose as to the fairest way of dividing them, and the savages
agreed to settle it by a game of chance—which was probably
“seven-up.” Mendez took advantage of the quarrelling to which the
game gave rise, and ran away. At the end of a fortnight he appeared
before the Admiral and announced that all was lost except honor and
his canoe.
The bold Mendez was not disheartened, but volunteered to
make a second attempt. This time he was joined by Fresco, the
captain of the other wreck, together with twelve Spaniards and
twenty Indians. The expedition started in two large canoes, and the
Adelentado, with an armed force, marched along the shore as far as
the extreme eastern point of the island to protect the canoes from
any attack by the natives. Mendez and his companions suffered
terribly from exposure and thirst, and many of the Indian paddlers
died—a fact which shows either that the Spaniards could endure
thirst better than the Indians, or that the latter had less water to drink
than the former.
The expedition finally reached Hispaniola, having formed a very
low opinion of canoeing as an athletic sport. According to the original
plan, Mendez was to induce Ovando to send a ship to Columbus,
and Fresco was to return with the news that Mendez was at San
Domingo, hard at work inducing the Governor to send the ship; but
as the surviving Indian paddlers said they were satiated with
paddling and did not intend to return to Jamaica, Fresco was
compelled to remain in Hispaniola.
Ovando, hearing that Columbus was in Jamaica, thought he had
better stay there, and instead of sending a vessel to his relief,
constantly promised to do so at the earliest possible moment, and
constantly took good care that no such moment should arrive.
Meanwhile the shipwrecked men were becoming very
discontented. When a man has nothing to do but to think of what he
is to have for dinner, and then never has it, he is reasonably sure to
exhibit a fretful spirit. This was the condition of the Spaniards at Port
Santa Gloria. They were living on board the wrecked vessels
because they did not care to tempt the appetites of the natives by
living on shore; and as the Admiral was confined to his cabin with the
gout, and could not overhear them, they naturally relieved their
minds by constantly abusing him, one to another.
Francesco de Porras, who had been a captain of one of the
ships—and it really seems as if there were as many captains in
proportion to the size of the fleet as there are in the United States
navy—thought this was a favorable time for mutiny, and accordingly
proceeded to mutiny. He reminded the men that Columbus was
unpopular in Spain, and was forbidden to land in San Domingo. This
being true, why should he ever leave Jamaica, where he had nothing
to do except to lie in his cabin and enjoy the pleasures of gout? He
insisted that Mendez and Fresco would never return, and that they
were either drowned or had gone to Spain. In short, by lucid
arguments such as these he convinced the crews that Columbus
intended to keep them in Jamaica for the rest of their lives.
Having thus induced the crews to mutiny, Porras went into the
Admiral’s state-room and demanded that he should instantly lead the
Spaniards back to Spain. Columbus took the ground that this was an
unreasonable demand, since an ocean voyage could not be
successfully made without vessels; but Porras, disgusted with such
heartless quibbling, rushed on deck and called on his followers to
embark in canoes and start for Cadiz without a moment’s delay. His
proposal was enthusiastically received, and a tumult ensued which
brought the crippled Admiral on deck on his hands and knees, in the
vain hope of enforcing his authority.
It was hardly to be expected that in such an attitude he could
strike the mutinous sailors with awe. Indeed, the probability that they
would strike him instead was so great that the Adelentado had his
brother carried back to the cabin, and there stood on guard over him
as coolly as if he were not at the mercy of an armed mob.
The mutineers, to the number of fifty, seized on a fleet of canoes
and started for Spain by way of San Domingo. Twice they were
driven back, and the second time they gave up the attempt. They
then wandered through the island, robbing the natives and alleging
that they were very sorry to do so, but they were acting under
express orders from Columbus, and that, as disinterested friends of
the noble Jamaicans, their advice was that the Admiral should be
killed without delay.
Weeks and months passed by, and no word came from Mendez
and Fresco. The natives, finding the Spaniards at their mercy, made
a corner in provisions and refused to sell except at an exorbitant
price. Thus famine began to threaten the unfortunate explorers. It
was then that Columbus performed his celebrated eclipse feat. He
summoned the caciques, and told them that in view of the enormity
of their conduct it had been decided to withdraw the moon from
heaven, and that this purpose would be carried out at the end of
three days. The Admiral had, of course, looked into his Public
Ledger Almanac, and had noticed that a total eclipse of the moon,
visible throughout the Gulf States and the West Indies, would take
place on the night in question.
When the third night came, and the eclipse began, the Indians
were terribly frightened, and begged the Admiral to forgive them and
give them back their beloved moon. At first he refused to listen to
them, but when the eclipse reached its period of greatest
obscuration he relented, and informed them that, for the sake of the
young men and young women of Jamaica, to whom the moon was
almost indispensable, he would give them one more chance. The
natives, overwhelmed with gratitude, and determined not to lose the
moon if they could help it, brought all the provisions that the
Spaniards wanted.
This was the first instance of turning American celestial
phenomena to practical uses; but the example of Columbus has
since been followed with great success by our scientific men, who
induce the government to send them at vast expense to all parts of
the world, under the plausible pretext of superintending total eclipses
and transits of Venus.
Mendez had been gone eight months when a small vessel
entered the harbor where the shipwrecked vessels were lying. It
carried Don Diego de Escobar, bearer of despatches from Ovando to
Columbus. Ovando wrote promising to send a ship to rescue
Columbus and his companions as soon as he could find one suitable
for the purpose. Having delivered this message and received an
answer, De Escobar instantly sailed away, to the immense disgust of
everybody. He was not altogether a nice person, having been one of
Roldan’s gang whom Bobadilla had released from prison. The
Admiral could not help thinking that it was hardly delicate in Ovando
to select such a messenger, but it was still a satisfaction to know that
Mendez had reached San Domingo, and that in the course of a few
years Ovando might find it convenient to send the promised ship.
Columbus now thought it was a good time to offer an amnesty to
Porras and his companions, on condition that they would return to
duty. Porras rejected the offer with disdain. He informed his men that
it was only a trap set by the wily Italian to get them once more in his
power. When they timidly suggested that a messenger from Ovando
had really visited the Admiral, and that this looked as if negotiations
were in progress for the purpose of arranging for the rescue of the
expedition, Porras boldly insisted that the alleged messenger and
the vessel in which he was said to have arrived had no existence.
They were simply “materialized” by Columbus, who was a powerful
spiritual medium, and they had already vanished into the
nothingness from which they had been called.
Convinced by this able address, the mutineers decided to remain
under the leadership of Porras, who immediately marched with them
to attack the Admiral and to seize the stores that still remained. Don
Bartholomew met them, and after a hard fight completely defeated
them, taking Porras prisoner. The survivors gladly surrendered, and
Columbus magnanimously forgave them.
In June, 1503, two ships arrived from San Domingo. One had
been fitted out by Mendez, and the other by Ovando, who saw that
Columbus would be rescued, and that he might as well earn part of
the credit therefor. The Spaniards hurriedly embarked, and on the
23d of the month, after a stay of more than a year in Jamaica, they
sailed for San Domingo, where they arrived after a voyage of about
six weeks. Ovando professed to be exceedingly glad to meet the
Admiral, and told him that for the last six or eight months he had
been steadily occupied in wasting to a mere shadow, so anxious had
he been to find a favorable moment for deciding upon the propriety
of sending a vessel to the rescue of his distinguished friend.
Columbus received his explanation with politeness, remarking “Ha!”
and also “Hum!” at appropriate intervals, just to intimate that, while
he did not care to argue with Ovando, he was not quite so credulous
as some people imagined. The populace were disposed to overlook
their bad treatment of their former Governor, inasmuch as his arrival
at San Domingo was an interruption of the monotony of their life; so
they cheered him when he passed through the street, and gave the
old man the last glimpse of anything like popularity which he was to
see.
[Æt. 67; 1503–1506]
Columbus was not anxious to remain long in the island. His

business affairs were in an intricate state of confusion, and though a
large sum of money was due to him, he could not collect it. The
condition of the Indians filled him with grief. Under the rule of
Ovando they had been constantly driven to revolt by oppression, and
then mercilessly massacred, while the Spanish priests had
expended a great deal of firewood and worn out several full sets of
controversial implements, such as racks and thumbscrews, in
converting them to Christianity. Columbus saw that his discovery of
Hispaniola had led to the ruin and misery of its people, and he could
not remain in any comfort amid so much suffering. Porras had
already been sent as a prisoner to Spain, and on September 12th
Columbus followed him. Ovando had supplied two vessels, one
commanded by Columbus and the other by Don Bartholomew, but
one of them was soon sent back as being unseaworthy. After a
stormy voyage the ship arrived at San Lucas on November 7th, and
the sick and crippled Admiral was carried to Seville, where he
intended to rest before proceeding to court.
This time he was not received with any enthusiasm. He had so
often returned from voyages to China without bringing with him so
much as a broken tea-cup as a sample of the Celestial Kingdom,
that the public had lost all interest in him. People who read in their
newspapers among the list of hotel arrivals the name of Columbus,
merely remarked, “So he’s back again it seems,” and then
proceeded to read the criticism upon the preceding night’s bullfight.
The popular feeling was, that Columbus had entirely overdone the
matter of returning home from profitless explorations. There were
other explorers who came back to Spain with stories much more
imaginative than those which Columbus could tell, and the Spanish
public had turned its attention from Prester John and the Emperor of

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55 Cases in Neurology Case Histories

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https://doi.org/10.1017/9781009214131.003 Published online by Cambridge University Press

1871. Three common mutations in the mitochondrial genome (m.3460G>A, m.11778G>A

https://doi.org/10.1017/9781009214131.003 Published online by Cambridge University Press

https://doi.org/10.1017/9781009214131.003 Published online by Cambridge University Press

https://doi.org/10.1017/9781009214131.004 Published online by Cambridge University Press

https://doi.org/10.1017/9781009214131.004 Published online by Cambridge University Press

Table 3.1 CSF findings

Measurement (normal range) LP 1 LP 2 (two weeks later)

https://doi.org/10.1017/9781009214131.004 Published online by Cambridge University Press

Diagnosis: Susac Syndrome

History of Susac Syndrome

Pathophysiology of Susac Syndrome

https://doi.org/10.1017/9781009214131.004 Published online by Cambridge University Press

Pathognomonic MRI Findings in Susac Syndrome

Management of Susac Syndrome