Clinical/Scientific Notes
Aneurysmal subarachnoid leak with
normal CT and CSF spectrophotometry
Mark O. McCarron, MA, MRCP, MD; and
Kishor A. Choudhari, MCh, FRCS(SN)
Subarachnoid hemorrhage (SAH) can be identified in 95% of patients with CT performed within 1 day of the ictus. If CT scanning is
negative, but the clinical suspicion of SAH remains, then lumbar
puncture (LP) after 12 hours with appropriate spectrophotometric
analysis for bilirubin in CSF is recommended. Xanthochromia, defined as spectrophotometric absorption measurements exceeding
0.023 at wavelength 415 nm or a peak in the absorption curve in the
450- to 460-nm range or both, was identified in all CT-positive patients with SAH when the CSF was analyzed within 2 weeks of
SAH.1 The authors concluded that an LP performed after 12 hours
and within 2 weeks of symptom onset would identify all of the CTnegative patients with SAH.1
Case report. A 29-year-old man developed sudden, severe pain
around his neck and throat while defecating. The pain radiated
down to his shoulders and up to his vertex. He described the pain
as the “worst pain” he had ever experienced. By the next morning,
he described his neck as “stiff.” During the following week, he had
ongoing headache with episodes of vomiting and sweating. There
was a previous history of migraine, which was different from his
presenting complaint (occipital pain, nausea, and vomiting, which
resolved within 2 days). He was admitted to the hospital on day 7.
Blood pressure on admission was 170/125 mm Hg. CT scan of
brain with and without contrast agent revealed no abnormality.
LP on day 8 revealed ⬍1 white cell/␮L, 6 red cells/␮L, 0.39 g/L
protein, and 3.3 mmol/L glucose. CSF net bilirubin absorbance
was ⬍0.007, suggesting no evidence of SAH.
The patient’s blood pressure was investigated and treated. On
day 13, he was referred to a neurologist. He still had headache
with exacerbations. Neurologic examination was normal. MRI of
the brain including fluid-attenuated inversion recovery sequences
was normal. An MR angiogram demonstrated a 4-mm aneurysm
of the right middle cerebral artery. After discussing treatment
options, the patient consented to surgical clipping of the aneurysm. At operation, there was evidence of an old hemorrhage in
the form of yellow discoloration of the arachnoid in the sylvian
fissure. The aneurysm was thin walled, and there was a remnant
of a thin small clot capping the dome. The patient had an uneventful postoperative recovery. Six months later, he was asymptomatic, had returned to work, and was normotensive on treatment.
Discussion. Warning headaches have been reported in 30 to
60% of patients who have had SAH. Although unruptured aneurysms can cause symptoms due to thrombosis, embolism, or mass
effect,2 sentinel headache due to hemorrhage has rarely been documented. In one autopsy report, there was leakage of blood
through a previous small tear in the wall of a saccular aneurysm
as well as a fresh fatal rupture at the fundus of the aneurysm.3 In
many patients, however, rebleeding may occur at the same tear as
the putative sentinel leak, rendering it impossible at autopsy to
distinguish sentinel hemorrhage from rehemorrhage. The lack of
definitive evidence of sentinel leaks, other potential mechanisms

“Levodopa phobia”: A new iatrogenic
cause of disability in Parkinson disease
Roger Kurlan, MD
Two recent research directions have raised question about the role
of levodopa in treating Parkinson disease (PD). First is evidence
that levodopa is toxic in nigral neuronal cell cultures.1 Second are
clinical trials showing that compared to beginning therapy with a
dopamine agonist, initial treatment with levodopa is associated
with earlier appearance of dyskinesias and wearing-off fluctuations.2,3 There has been much publicity about these potential negative aspects of levodopa. I report two patients with PD who

for aneurysms to cause symptoms, and the lack of focal hemorrhage recorded at surgery have led to “sentinel hemorrhage” skepticism. Patients with first-ever acute, severe headache presenting
with SAH without loss of consciousness or focal deficits had no
clinical or radiologic differences from SAH patients who had a
preceding bout of headache. Some of these headaches may be due
to recall bias.4 Long-term follow-up of patients with thunderclap
headache investigated with negative CT and CSF findings suggests a benign outcome.
There are a few reports of thunderclap headache in patients
with an unruptured aneurysm.2,5,6 In some patients, vasospasm
has been identified at angiography. No evidence of old or recent
hemorrhage was found on CT or CSF analysis or at operation.5,6
“Minor leak” aneurysmal hemorrhage was documented in 8 of
46 Japanese patients with a normal CT scan of the brain.7 Seven
of the eight patients had headache for ⬎24 hours. They all had a
“normal CSF color.” Our findings suggest that a false-negative
CSF bilirubin determination (which is more sensitive than visual
inspection) can occur within the recommended investigative timeframe with a history suspicious for SAH. The location of the aneurysm, particularly within the sylvian fissure, loculation of blood,
and the small amount of hemorrhage are possible explanations for
this finding.
Most patients with SAH but negative CT appear to be accurately diagnosed with appropriately timed CSF bilirubin determination.1 Our observation is insufficient per se to alter current
management protocols for patients with suspected SAH, although
neuroimaging advances may improve detection of small SAHs.
From the Department of Neurology (Dr. McCarron), Altnagelvin Hospital,
Londonderry, and Department of Neurosurgery (Dr. Choudhari), Royal Victoria Hospital, Belfast, UK.
Received July 21, 2004. Accepted in final form October 19, 2004.
Address correspondence and reprint requests to Dr. M.O. McCarron, Department of Neurology, Altnagelvin Hospital, Londonderry, BT47 6SB, UK;
e-mail: markmccarron@doctors.org.uk
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Vermeulen M, Hasan D, Blijenberg BG, Hijdra A, van Gijn J. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol
Neurosurg Psychiatry 1989;52:826 – 828.
2. Raps EC, Rogers JD, Galetta SL, et al. The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol 1993;50:265–268.
3. Ball MJ. Pathogenesis of the “sentinel headache” preceding berry aneurysm rupture. Can Med Assoc J 1975;112:78 –79.
4. Linn FH, Rinkel GJ, Algra A, van Gijn J. The notion of “warning leaks”
in subarachnoid haemorrhage: are such patients in fact admitted with a
rebleed? J Neurol Neurosurg Psychiatry 2000;68:332–336.
5. Day JW, Raskin NH. Thunderclap headache: symptom of unruptured
cerebral aneurysm. Lancet 1986;2:1247–1248.
6. Witham TF, Kaufmann AM. Unruptured cerebral aneurysm producing a
thunderclap headache. Am J Emerg Med 2000;18:88 –90.
7. Takeuchi T, Kasahara E, Iwasaki M, Kojima S. Necessity for searching
for cerebral aneurysm in thunderclap headache patients who show no
evidence of subarachnoid hemorrhage: investigation of 8 minor leak
cases on operation. No Shinkei Geka [Neurol Surg]1996;24:437– 441.
Japanese.

became disabled because their treating neurologists were fearful
of prescribing levodopa because of the widespread publicity.
Case reports. Case 1. A 72-year-old man had been diagnosed
with PD 3 years earlier. He was initially treated with ropinirole
and required steadily increasing dosages up to 24 mg/day. Due to
ongoing bradykinesia and gait difficulties, amantadine 300 mg/
day and deprenyl 10 mg/day were added. Visual hallucinations
and episodes of confusion developed but resolved after discontinuation of amantadine and deprenyl. The patient was functionally
disabled by unsteady gait with freezing, overall slowness, and
impaired dexterity for daily activities such as dressing and eating
and was referred to the University of Rochester PD Program by
the treating neurologist “since there are no other medication opMarch (1 of 2) 2005

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tions.” Examination was compatible with moderate idiopathic PD.
Ropinirole was reduced to 9 mg/day and levodopa (with carbidopa)
was titrated over 3 weeks to 600 mg/day. Gait, bradykinesia, and
other motor function improved substantially and this improvement has been maintained for 9 months with no tolerability
problems.
Case 2. A 62-year-old man had been diagnosed with PD 6
years earlier. He was treated with deprenyl 10 mg/day and levodopa (with carbidopa) 300 mg/day and did well for 4.5 years. He
then developed “wearing off” motor fluctuations, start hesitation,
and gait imbalance. The addition of entacapone 600 mg/day produced mild but unsatisfactory benefit. Levodopa was adjusted to
150 mg at 7:00 AM, 150 mg at 10:00 AM, and 100 mg at 2:00 PM.
The patient was slow but had adequate mobility most days from
about 8:00 AM to 3:00 PM but was bedridden in an akinetic “off”
state at all other times. He stopped working due to this medical
disability. He was referred to the University of Rochester PD
Program by the treating neurologist “because I don’t want to use
more than 400 mg/day of levodopa and I know it’s best to use as
little medication as possible.” Examination was compatible with
moderate idiopathic PD. Over the next 6 weeks, levodopa was
adjusted to 150 mg every 3 hours (7:00 AM to 10:00 PM; 900 mg/
day), entacapone 200 mg and pramipexole 0.25 mg were given
with each levodopa dose, and deprenyl was reduced to 5 mg/day.
Motor fluctuations largely resolved and there was substantial improvement in overall function that has been maintained for 6
months. The patient has returned to work.
Discussion. While recent research regarding levodopa appears to have influenced treatment practices, it remains controversial and it is unclear if its effects on clinical practice are
justified. While the in vitro study suggested levodopa neurotoxicity, there is no current evidence that this translates to the human
disease.1 A recently published trial found no clinical or neuroimaging evidence that early use of levodopa, even in high dosages,
adversely impacts the illness.4 Several commentaries with different interpretations of the early levodopa vs dopamine agonist
trials have been published5,6 and the Practice Parameters Committee of the American Academy of Neurology concluded that

initial symptomatic treatment with a dopamine agonist or levodopa is appropriate.7
Currently available scientific data do not appear to justify the
practice of neurologists withholding adequate levodopa therapy,
particularly for patients with substantial functional disability.
The “Sinemet scare” has become an unjustified iatrogenic cause of
disability in PD. Similarly, the fear of levodopa induced by publicity has led some disabled patients with PD to avoid the drug
inappropriately.

Palatal myoclonus in a patient with a lateral
thalamic infarction

the deep (thalamogeniculate pedicle) and superficial branches of
the posterior cerebral artery. No medullary lesions were present.
We performed an EEG-polygraphic recording including 16
EEG channels, EKG recording, 4 EMG channels (flexor and extensor muscles of both forearms) that revealed the presence of rhythmic contractions involving simultaneously the flexor and the
extensor muscles of the right hand, without related EEG abnormalities. Back averaging of myoclonic jerks was performed, confirming the absence of a cortical potential time locked with EMG
potentials. No features of negative myoclonus were present at the
polygraphic study. Somatosensory evoked potentials were normal.
An EKG revealed the presence of atrial fibrillation while transthoracic and transesophageal echocardiograms showed a slight dilatation of the left atrium. Routine blood and coagulation tests were
normal. At discharge, both PM and the upper limb myoclonus
were still present. Two years after the stroke, PM was still evident
while the extremity myoclonus had disappeared.
Discussion. We describe PM in a patient with a lateral thalamic infarction, which was associated with a synchronous upper
limb myoclonus. Several abnormal involuntary movements have
been reported in patients with thalamic infarction,6,7 particularly
involving the lateral portion. PM (either isolated or associated to
extremity myoclonus) has almost exclusively been described in
patients with lesions involving the Guillain–Mollaret triangle.5
The presence of a complex myoclonus in a patient with a lateral thalamic infarction raises some questions regarding the
pathogenetic mechanism. If the upper limb myoclonus might be
explained by the impairment of the cerebellar efferent pathway at
the level of the ventrolateral nucleus, it is difficult to explain the
PM in absence of brainstem or cerebellum lesion. It is well known
that the central tegmental tract descending in the dorsal brainstem from the red nucleus to the inferior olive is relevant for the
occurrence of the PM. Moreover the impairment of the CTT may
cause a disinhibition of the inherent activity of the cells within the
inferior olive which, according to animal studies, expose a spontaneous activity at a frequency between 0.5 and 3 Hz. In our pa-

P. Cerrato, MD; M. Grasso, MD; C. Azzaro, MD; C. Baima, MD;
A. Lentini, MD; M. Giraudo, MD; E. Montalenti, MD; and
B. Bergamasco, MD
Palatal myoclonus (PM) is characterized by rhythmic involuntary
jerking movement of the soft palate and the pharyngopalatine
arch, often involving the diaphragm and laryngeal muscles.1
The two distinct clinical entities, symptomatic PM and essential PM, arise from different pathophysiologic mechanisms.2
Symptomatic PM is usually associated with lesions located in
the myoclonic triangle (the Guillain–Mollaret triangle). It consists
of the red nucleus, inferior olive, contralateral cerebellar dentate
nucleus, and the connecting pathways, namely the central tegmental tract, the inferior cerebellar peduncle, and superior cerebellar peduncle.3 Symptomatic PM may be isolated or more rarely
associated with movements of the extremities such as tremor,
choreoathetosis, and myoclonus.4,5
Case report. A 64-year-old man was referred for acute onset
of motor impairment of the right arm. On admission neurologic
examination revealed clumsiness of the right arm and right dysmetria on finger-to-nose test. On the fifth day the patient developed myoclonic movements of his right arm consisting of rhythmic
flexion of the hand over the forearm. The myoclonus was absent at
rest and was elicited only with right hand outstretched. In the
meantime rhythmic involuntary jerking movements of the soft
palate and the pharyngopalatine arch (palatal myoclonus) were
noted. The patient was unaware of his PM. Myoclonic movements
of the right hand were synchronous with the PM and had a frequency of 0.5 Hz.
On admission a cranial CT scan and extracranial Doppler ultrasonography were normal. Three days later, a brain MRI revealed two ischemic lesions involving the lateral portion of the left
thalamus (figure) and the medial temporal lobe in the territory of
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March (1 of 2)

From the Department of Neurology, University of Rochester School of Medicine, NY.
Received September 16, 2004. Accepted in final form November 1, 2004.
Address correspondence and reprint requests to Dr. Kurlan, Department of
Neurology, University of Rochester School of Medicine, Rochester, NY 14642;
e-mail: Roger_Kurlan@urmc.rochester.edu
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Fahn S. Levodopa-induced neurotoxicity: does it represent a problem for
the treatment of Parkinson’s disease? CNS Drugs 1997;8:376 –393.
2. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for
Parkinson disease—a randomized controlled trial. JAMA 2000;284:
1931–1938.
3. Rascol O, Brooks DJ, Korczyn AD, DePeyn PP, Clarke CE, Lang AE. A
five-year study of the incidence of dyskinesia in patients with early
Parkinson’s disease who were treated with ropinirole or levodopa.
N Engl J Med 2000;342:1484 –1491.
4. Fahn S, Parkinson Study Group. Evaluation of the long-duration benefit
from levodopa: results from the ELLDOPA (Earlier vs. Later Levodopa)
study. Mov Disord 2003;18:1085–1086.
5. Albin RC, Frey KA. Initial agonist treatment of Parkinson’s disease. A
critique. Neurology 2003;60:390 –394.
6. Ahlskog JE. Slowing Parkinson’s disease progression. Recent dopamine
agonist trials. Neurology 2003;60:381–389.
7. Miyasaki JM, Martin W, Sucherowersky O, Weiner WJ, Lang AE. Practice parameter: Initiation of treatment for Parkinson’s disease: an
evidence-based review. Report of the Quality Standards Subcommittee of
the American Academy of Neurology. Neurology 2002;58:11–17.

Figure. Magnetic resonance scan, (A)
axial, T2-weighted (3,800/120/2 repetition time/echo time/excitations) and (B)
coronal, T2-weighted (3,800/120/2). A
round hyperintense lesion is located in
the lateral portion of the left thalamus
(A). The ischemic lesion involves the
lateral thalamus (B) in the territory of
the thalamogeniculate arteries arising
from the posterior cerebral artery.

tient, we hypothesize an influence of the lateral thalamus on the
red nucleus located in the upper mesencephalon. Indeed the presence of descending thalamo-rubral fibers has been reported in old
neuroanatomic studies but not in the more recent investigations
and is in contrast with the accepted notion that there is an absence of any descending fibers from the thalamus to the
brainstem.
However, the concomitance of upper limb myoclonus, cerebellar signs, and PM may suggest a unique pathogenetic mechanism
related to the lesion of the ventrolateral thalamus and the cerebellar circuit.
From the First Division of Neurology and Foundation S. Maugeri (Pavia),
University of Turin, Italy.
Received August 4, 2004. Accepted in final form October 28, 2004.
Address correspondence and reprint requests to Dr. B. Bergamasco, First
Division of Neurology and Foundation S. Maugeri (Pavia), University of
Turin, Via Cherasco 15, 10126 Torino, Italy.

Different pain patterns in patients with
vertebral artery dissections
J.E. de Sousa, MD; M.J. Halfon, MD; P. Bonardo, MD;
R.C. Reisin, MD; and M.M. Fernández Pardal, MD
Spontaneous or traumatic cervical artery dissections are an increasingly recognized cause of stroke in young adults.1 The internal carotid artery (ICA) is more frequently involved than the
vertebral artery (VA).1 Headache and neck pain are common and
suggestive symptoms of VA dissection (VAD).2 However, their clinical characteristics and their relationship with focal neurologic
symptoms have not been extensively analyzed.
Methods. We prospectively analyzed 10 consecutive patients
admitted to our hospital with diagnosis of VAD from 1995 to 2003.
In all cases, the dissection was confirmed by magnetic resonance
angiography (MRA), conventional angiography, or both. The presence of headache, neck pain, or both at the time of the dissection,
their characteristics, and their association with neurologic signs
and symptoms were registered by direct interview. The history of
headache was classified according to the International Headache
Society criteria.3 Headache at the time of arterial dissection was
classified into that occurring before, during (within 30 minutes of
the focal symptoms), or after other clinical manifestations.
Case report. A 48-year-old man with no history of migraine
was admitted to the hospital because of thunderclap headache
with left hemicranial and posterolateral neck pain and clinical
signs of Wallenberg syndrome. He reported three previous episodes of severe left hemicranial headache lasting 2 hours in the
last 48 hours before admission. MRI showed left lateral medullary
infarct, and MRA revealed left V1 to V4 VAD.
Results. Ten patients fulfilled diagnostic criteria of VAD (six
men; mean age 54.3 years, range 30 to 67 years). Dissection was
traumatic in only one patient. Pain (headache, neck pain, or both)

Copyright © 2005 by AAN Enterprises, Inc.

References
1. Lapresle J, Ben Hamida M. The dentate-olivary pathway. Arch Neurol
1970;22:135–145.
2. Deschl G, Toro C, Valls-Solè J, et al. Symptomatic and essential palatal
tremor. Brain 1994;117:775–788.
3. Guillain G, Mollaret P. Deux cas de myoclonies synchrones et rythmees
vel-pharyngo-laryngo-oculo-diaphramatiques. Le probleme anatomique
et physiopathologique de ce syndrome. Rev Neurol 1931;2:545–556.
4. Masucci E, Kurtzke J. Palatal myoclonus associated with extremity
tremor. J Neurol 1989;236:474 – 477.
5. Tahmoush AJ, Brooks JE, Keltner JL. Palatal myoclonus associated with
abnormal ocular and extremity movements. Arch Neurol 1972;27:431–
440.
6. Lehericy S, Grand S, Pollak P, et al. Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology 2001;57:1055–1066.
7. Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical syndrome,
etiology, and prognosis. Neurology 1988;38:837– 848.

was present in all patients; it was the first symptom of VAD in six
patients. It affected the posterolateral aspect of the neck in eight.
Headache was present in eight patients; it was hemicranial in
four, occipital in three, and frontoparietal in one. Headache preceded other clinical manifestation in five patients, was simultaneous with other manifestations in two, and developed after
neurologic deficit in the remaining patient. Only one patient had a
history of migraine. No patient had subarachnoid hemorrhage. All
patients were anticoagulated.
We identified two groups according to the temporal pattern of
pain:
Group 1 (continuous pain pattern). In five patients (mean age
59.6 years), pain was continuous: bioccipital in two, located in the
neck in one, and headache and neck pain in two. Mean pain
intensity was 6 of 10, and mean pain duration was 26.4 hours.
Mean time from pain onset to VAD diagnosis was 3.1 days (range
0 to 9 days). Dissection affected the V4 segment in two patients.
Three patients experienced a cerebellar infarct, and the remaining
two developed a Wallenberg syndrome. All patients recovered
completely.
Group 2 (intermittent pain pattern). In five patients (mean
age 49 years), pain attacks were separated by pain-free periods.
Four patients had hemicranial headache associated with neck
pain, and one patient had neck pain only. Mean pain intensity
was 7 of 10 with a mean duration of 4.6 hours. Mean time from
pain onset to VAD diagnosis was 7.7 days (range 0.5 to 15 days).
Mean number of pain attacks was 5.4, and pain-free periods
lasted up to 34 hours. Dissection affected the V4 segment in all
patients. Three patients showed a Wallenberg syndrome, and the
remaining two experienced a cerebellar infarct. Two patients had
disabling sequelae.
Discussion. Headache is a cardinal manifestation of ICA and
VA dissections.2 The most common syndrome in VAD is unilateral,
typically occipital headache with or without ipsilateral neck pain
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925

followed by ischemic symptoms in the vertebrobasilar distribution.2,4 Pain may be explained by the fact that dissection affects
the upper cervical nerves that innervate the vasculature of the
posterior fossa.5 Nevertheless, asymptomatic progression of the
arterial dissection in the acute phase1 and asymptomatic recurrences have been reported.6
The main finding of our study is that 50% of our patients with
VAD showed a headache pattern consisting of recurrent pain attacks separated by pain-free periods.
ICA dissection may occur in steps.7 Pain in the neck may be
present for days or may recur days or even weeks later, accompanied by TIAs or strokes. The explanation proposed is that the
initial tear extends and intramural bleeding enlarges when the
symptoms worsen.7 It is likely that the same mechanism might be
implicated in VAD with a pattern of recurrent pain attacks, as
suggested by our results.
Although the small number of patients is a shortcoming of this
study, our findings suggest that intermittent pain pattern is not
infrequent in VAD and might be associated with hemicranial
headache, younger age, delayed diagnosis (probably due to the
presence of pain-free intervals), intracranial extension of VAD,
and worse prognosis.
From the Department of Neurology, Hospital Británico de Buenos Aires,
Argentina.

Severe sensory neuropathy associated with
long-term linezolid use
Sasa A. Zivkovic, MD; and David Lacomis, MD
Linezolid is an antibiotic used for treatment of drug-resistant
gram-positive micro-organisms. It is recommended to treat patients with linezolid for up to 28 days,1 but sometimes it is used
for a longer period of time in the treatment of bone infections. It is
usually well tolerated, and few patients develop myelosuppression, diarrhea, or nausea.1 However, recent reports indicate a risk
of a potentially irreversible neuropathy following prolonged use.2-5
We report an additional patient with severe sensory polyneuropathy following a 6-month course of linezolid.
Case report. A 42-year-old, otherwise healthy woman sustained left ankle, tibia, femur, pelvic, and rib fractures in a motor
vehicle accident in December 1999. Subsequently, she underwent
multiple orthopedic surgeries, complicated by treatment-resistant
staphylococcal osteomyelitis. In May 2001, she was treated with
linezolid 600 mg bid orally. This drug was continued until November 2001. In June 2001, she had lower extremity numbness. Electrodiagnostic studies showed absent medial and lateral plantar
and sural sensory responses and were otherwise unremarkable.
However, a few months later, she gradually developed progressive
weakness and numbness of the lower and upper extremities, ac-

Received August 24, 2004. Accepted in final form November 3, 2004.
Address correspondence and reprint requests to Dr. M.J. Halfon, Neurology
Department, Hospital Británico de Buenos Aires, Perdriel 74, Buenos Aires,
CP: C1280AEB, Argentina; e-mail: mjhalfon@yahoo.com
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;344:898 –906.
2. Silbert PL, Mokri B, Schievink WI. Headache and neck pain in spontaneous internal carotid and vertebral artery dissections. Neurology 1995;
45:1517.
3. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988;8:1–96.
4. Mokri B, Houser OW, Sandok BA, Piepgras DG. Spontaneous dissections
of the vertebral arteries. Neurology 1988;38:880 – 885.
5. Moskowitz MA. Pain mechanisms underlying vascular headaches:
progress report 1989. Rev Neurol (Paris) 1989;145:181–193.
6. Touzé E, Oppenheim C, Zuber M, Méary E, Meder JF, Mas JL. Early
asymptomatic recurrence of cervical artery dissection. Neurology 2003;
61:572–574.
7. Caplan LR. Caplan’s stroke: a clinical approach. 3rd ed. Cambridge, UK:
Butterworth-Heinemann, 2000.

companied by right facial numbness and blurred vision. She was
admitted to the hospital in November 2001. By that time, her
vision had improved, and she had severe acral burning pain and
numbness. She did not abuse alcohol, and there was no family
history of neuropathy. On examination, she had severe sensory
loss to all modalities extending up to the knee and elbow levels.
Vibration sense and proprioception were more severely affected
than sensation to light touch, cold, and pinprick. Deep tendon
reflexes were 1 of 4 in the upper extremities and absent in the
legs. Strength examination was limited by orthopedic instrumentation, but she had only mild distal weakness of right foot dorsiflexors and bilateral finger extensors (Medical Research Council
4/5). Coordination was normal. She was ambulating with
crutches. Fundoscopy revealed retinal vein engorgement, and visual acuity was 20/40 bilaterally.
Laboratory studies included normal CSF studies, normal vitamin B12 and glucose levels, and negative anti-Hu, anti-Yo, and
SS-A/B antibody titers. Lip biopsy was negative. MRI studies of
total spine, brain, and optic nerve were normal. Electrodiagnostic
studies demonstrated severe sensory neuropathy (or ganglionopathy) (table), without motor involvement and with a normal needle
examination. The patient declined a nerve biopsy. Outpatient and
electrodiagnostic follow-up over 20 months revealed no changes.
Discussion. Toxic neuropathies usually improve after the offending agent is removed or after a period of “coasting.” However,

Table Nerve conduction studies
Amplitude (normal), ␮V

Peak distal latency (normal), ms

Sural

NR

NR

Superficial peroneal

NR

NR

Median

1 (⬎20)

3.6 (⬍3.4)

Ulnar

NR

NR

Radial

NR

NR

Sensory nerves

Amplitude
(normal), mV

Distal latency
(normal), ms

Conduction velocity
(normal), m/s

F-wave latency
(normal), ms

Peroneal

5.7 (⬎2.5)

4.3 (⬍5.5)

41 (⬎40)

46.9 (⬍55)

Tibial

15.1 (⬎8)

3.5 (⬍6.0)

41 (⬎40)

45.9 (⬍57)

Median

6.6 (⬎6)

3.3 (⬍3.9)

54 (⬎50)

26.7 (⬍31)

Ulnar

9.1 (⬎7)

2.2 (⬍3.1)

56 (⬎50)

26.2 (⬍33)

Motor nerves

NR ⫽ no response.
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if the dorsal root ganglia are affected, sensory neuro(no)pathy may
be irreversible.6 Eighteen cases of possible toxic linezolidassociated peripheral neuropathy have been described in the literature,3 but it is probably more common as more cases were
reported to drug-monitoring agencies or electronic mailing lists.2,3
The severity and persistence of sensory neuropathic symptoms
following linezolid treatment indicate possible ganglionopathy.2-5
Notable is the frequent occurrence of optic neuropathy, suggesting
common mechanisms of neurotoxicity.2,3,7 Concomitant optic neuropathy may improve before peripheral neuropathy.2 Our patient
might also have had optic neuropathy, but her visual symptoms
had already improved,.
Peripheral neuropathy associated with linezolid has predominant sensory involvement with profound loss of vibration sense
and proprioception, burning pain, and only minor weakness. In
most patients, symptoms do not improve after medication is
stopped. Electrodiagnostic studies are consistent with axonal or
ganglion cell injury, affecting predominantly sensory nerve fibers.
Affected patients were treated with linezolid for 4 to 6 months,
much longer than the recommended 28 days, suggesting a threshold effect.1-5 Mechanisms of nerve injury by linezolid remain unclear. Linezolid blocks bacterial protein synthesis by binding to
ribosomal proteins; it has been speculated that neurotoxicity may
be related to mitochondrial dysfunction, but histopathologic studies are lacking.3,7
Our case expands the spectrum of sensory neuro(no)pathy and
demonstrates the need to closely monitor patients treated with
long-term linezolid therapy as neuropathy may be irreversible.

Electrophysiology extends the phenotypic
spectrum of X-linked myopathy with
excessive autophagy
I. Munteanu, MD; C.A. Ackerley, PhD; G.N. Mnatzakanian, BSc;
J.T. Kissel, MD; and B.A. Minassian, MD
X-linked myopathy with excessive autophagy (XMEA) (MIM
310440) is an X-linked recessive boyhood-onset disorder of skeletal
muscle with a slowly progressive course toward wasting of proximal muscles of the lower extremities and wheelchair dependency
by the fifth decade of life. Involvement of distal leg muscles and
upper extremities is clinically evident late in the disease.1-4 Skeletal muscle pathology is characterized by a constellation of rare
and unique features. Autophagic vacuoles containing cellular debris are present in the sarcoplasm, and at the sarcolemma extruding their contents to the extracellular space. Myofibers containing
vacuoles have multiple layers of basement membrane. Intense
calcium accumulation is seen at the myofiber periphery, in the
absence of necrosis. Extensive deposition of complement membrane attack complex (MAC) is present at the myofiber surface,
without resultant cell lysis. Finally, class I major histocompatibility complex is expressed, despite the absence of inflammation.1-4
Nerve conduction studies (NCS) are normal but EMG reveals
myopathic changes, including striking myotonic and highfrequency discharges, in the absence of any clinical myotonia, in
all muscles, even clinically unaffected facial, bulbar, and distal
limb muscles.5 In the present work, we demonstrate that XMEA
can manifest with the EMG abnormalities alone, without the clinical syndrome.
Methods. Two apparently unrelated American families (Families E and B; see figure E-1 on the Neurology Web site at www.
neurology.org) with XMEA have been followed by one of the authors (J.T.K.) for 20 years. All eight clinically affected members of
these families (black squares in figure E-1) are following a similar
clinical course with onset of weakness in mid to late childhood,
obvious lower limb girdle muscle atrophy by mid to late adolescence, and severe wasting requiring Gower’s type maneuvers to
rise from a seated position, and ambulatory walking aids by the

Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 8 issue to find the title link for this article.

Further studies are needed to fully elucidate the pathophysiology
and mechanisms of linezolid-related nerve injury.
From the Departments of Neurology (Drs. Zivkovic and Lacomis) and Pathology (Neuropathology) (Dr. Lacomis), University of Pittsburgh School of
Medicine, PA.
Received October 4, 2004. Accepted November 1, 2004.
Address correspondence and reprint requests to Dr. S.A. Zivkovic, Department of Neurology, University of Pittsburgh Medical Center, 3471 Fifth Ave.,
811, Pittsburgh, PA 15213; e-mail: zivkovics@upmc.edu
Copyright © 2005 by AAN Enterprises, Inc.

References
1. French G. Safety and tolerability of linezolid. J Antimicrob Chemother
2003;51(suppl 2):ii45–ii53.
2. Corallo CE, Paull AE. Linezolid-induced neuropathy. Med J Aust 2002;
177:332.
3. Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy
associated with prolonged use of linezolid. Lancet Infect Dis 2004;4:528 –
531.
4. Rho JP, Sia IG, Crum BA, Dekutoski MB, Trousdale RT. Linezolidassociated peripheral neuropathy. Mayo Clin Proc 2004;79:927–930.
5. Spellberg B, Yoo T, Bayer AS. Reversal of linezolid-associated cytopenias, but not peripheral neuropathy, by administration of vitamin B6. J
Antimicrob Chemother 2004;54:832– 835.
6. Peltier AC, Russell JW. Recent advances in drug-induced neuropathies.
Curr Opin Neurol 2002;15:633– 638.
7. Lee E, Burger S, Shah J, et al. Linezolid -associated toxic optic neuropathy: a report of two cases. Clin Infect Dis 2003;37:1389 –1391.

30s. One patient in his 50s is wheelchair-dependent. The creatine
kinase (CK) levels in these patients, including the oldest, range
from 2 to 10 times the upper limit of normal. Their biopsies and
EMG exhibit the classic features of XMEA.6
The XMEA gene maps to one of the most gene-dense regions of
the genome, a 4.37 Mb region containing at least 110 genes, in
chromosomal band Xq287 (see figure E-1). We genotyped this region in Families E and B and noticed that the haplotypes of
affected individuals (boxed section, see figure E-1) are identical in
the two families, indicating a likely common founder, and common
mutation, in these two families. Genealogic review revealed that
each family had an ancestor who had migrated to the American
state of Ohio from present-day Slovakia in the 19th century. Work
is under way to determine whether a familial relationship exists
between these two individuals.
Results. The disease-associated haplotype was present in all
affected individuals, but surprisingly it was also found in two
apparently unaffected members of Family E (III-7 [58 years old]
and III-11 [41 years old]; see figure E-1). We reexamined these
two individuals clinically and found minimal, questionable, weakness in hip flexion and quadriceps function in Patient III-11 and a
CK three times higher than the upper limit of normal. The older
individual, III-7, continued to have normal strength in all muscle
groups with CK at the upper limit of normal. We then examined
both electrophysiologically, and obtained a quadriceps biopsy from
Patient III-11. NCS were normal, and needle examination (Vastus
Medialis and Lateralis and Tibialis Anterior) demonstrated increased insertional and abnormal spontaneous activities, and
complex repetitive and myotonic discharges. As negative controls,
we performed EMG studies in two unaffected age-matched male
relatives who do not carry the disease-associated haplotype, and
found no abnormalities. Pathologic analysis in Patient III-11 revealed very rare abnormal fibers (⬍5%), with telltale XMEA features: vacuolation and sarcolemmal and vacuolar staining with
MAC and dystrophin antibodies.
Discussion. In this study, we have documented clinical nonpenetrance, while demonstrating penetrance of the electrophysiologic
phenotype in XMEA. Absence of the clinical phenotype in some
XMEA patients invokes the presence of modifier genes, outside
the XMEA gene region, with protective effects against XMEA
myopathology. Presence of the EMG phenotype in all individuals
with the disease-associated haplotype suggests that it is an essential component of the syndrome. The EMG findings indicate myofiber membrane irritability throughout tested muscles despite the
rarity of pathologically affected fibers, supporting previous theories3,5 of a primary myofiber surface abnormality in the pathogenesis of XMEA.
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Refinement of the XMEA phenotypic spectrum will impact future genetic studies, including the correct assignment of affected
status to male subjects with recombinant chromosomes, necessary
to the narrowing of the XMEA gene region.
Acknowledgment
The authors thank the family members for their participation.
From the Program in Genetics and Genomic Biology (Drs. Munteanu and
Minassian and G.N. Mnatzakanian) and Department of Pathology and Laboratory Medicine (Dr. Ackerley), The Hospital for Sick Children, and Institute of Medical Sciences (Drs. Munteanu and Minassian), University of
Toronto, Ontario, Canada; and Department of Neurology (Dr. Kissel), The
Ohio State University, Columbus.
Supported by the CIHR-Neuromuscular Research Partnership (Canadian
Institute of Health Research, Amyotrophic Lateral Sclerosis Society of Canada, and Muscular Dystrophy Association of Canada).
Received August 26, 2004. Accepted in final form November 1, 2004.
Address correspondence and reprint requests to Dr. Berge A. Minassian,
Program in Genetics and Genomic Biology, The Hospital for Sick Children, and
Institute of Medical Sciences, University of Toronto, 555 University Ave., Toronto, Ontario M5G 1X8, Canada; e-mail: bminass@sickkids.ca

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March (1 of 2)

Copyright © 2005 by AAN Enterprises, Inc.

References
1. Kalimo H, Savontaus ML, Lang H, et al. X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 1988;23:
258 –265.
2. Villanova M, Louboutin JP, Chateau D, et al. X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of
injured muscle fibers. Ann Neurol 1995;37:637– 645.
3. Chabrol B, Figarella-Branger D, Coquet M, et al. X-linked myopathy
with excessive autophagy: a clinicopathological study of five new families. Neuromuscul Disord 2001;11:376 –388.
4. Minassian BA, Levy N, Kalimo H. X-linked myopathy with excessive
autophagy. In: Karpati G, ed. Structural and molecular basis of skeletal
muscle diseases. Zurich: ISN Neuropath Press, 2002;145–147.
5. Jaaskelainen SK, Juel VC, Udd B, et al. Electrophysiological findings in
X-linked myopathy with excessive autophagy. Ann Neurol 2002;51:648 –
652.
6. Mendell JR, Garcha TS, Kissel JT. The immunopathogenic role of complement in human muscle disease. Curr Opin Neurol 1996;9:226 –234.
7. Minassian B, Aiyar A, Alic S, et al. Narrowing in on the causative defect
of an intriguing X-linked myopathy with excessive autophagy. Neurology
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Palatal myoclonus in a patient with a lateral thalamic infarction
P. Cerrato, M. Grasso, C. Azzaro, et al.
Neurology 2005;64;924-925
DOI 10.1212/01.WNL.0000152870.07073.87
This information is current as of March 7, 2005
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