Clinical/Scientific Notes
Sea wave–induced internal carotid artery
dissection
R. Pego-Reigosa, MD, PhD; S. López-López, MD;
M.E. Vázquez-López, MD; V. Armesto-Pérez, MD;
F. Brañas-Fernández, MD; F. Martínez-Vázquez, MD, PhD;
R. Piñeiro-Bolaño, MD, PhD; and J.A. Cortés-Laiño, MD
Internal carotid artery dissection has been associated with trivial
trauma.1 We report a patient with internal carotid artery dissection related to a severe sea wave trauma to the cervical region.
Case report. A right-handed 56-year-old man presented to the
emergency room because of a 15-minute episode of dysarthria and
left-hand numbness. Earlier that day, he had been in the sea.
There was heavy surf with waves that were 0.5 to 1 m high. When
he was distracted and with his neck turned to the left, a wave
struck him, knocking him over. When he returned to shore, his
wife noticed that he was disoriented and confused. These symptoms lasted approximately 30 minutes, and he later presented to
the hospital with a transient neurologic deficit (outlined above)
and right-sided headache. He never smoked and had no personal
or family history of arterial dissection, connective tissue disease,
hypertension, or migraine. On neurologic examination at admission, he was alert and fully oriented and had a right ptosis and
miosis. The rest of the examination was normal. There were no
clinical signs suggesting hereditary connective tissue disease,
such as hypermobile joints, other limb and dermal abnormalities,
or blue sclera. Complete blood count and routine biochemistry
were unremarkable. Head CT was normal. MRI study (fluidattenuated inversion recovery, diffusion, and T1- and T2-weighted
sequences and MR angiography) showed an acute ischemic stroke
in the right middle cerebral artery territory and a hematoma in
the wall of the right internal carotid artery along with internal
carotid artery narrowing, consistent with arterial dissection (figure). The patient was diagnosed with TIA (although there was
radiologic evidence of infarction) secondary to a right carotid artery dissection. He was treated with sodium heparin for 7 days
and then discharged with oral warfarin.
Discussion. This patient experienced an internal carotid artery dissection probably related to the wave trauma, as there was
a clear relationship between this trauma and the onset of the
neurologic symptoms.
Traumatic dissection of the internal carotid artery has been
described in diverse situations: blunt trauma in road traffic accidents,1 sports (taekwondo, French horn, kickboxing, softball, etc.),2
airbag or seatbelt trauma,3,4 and strangulation.5 Occasionally, dissection is an incidental finding during radiologic screening of the
cervical spine and brain in severely injured patients.6
In our patient, the intensity of the injury may have been high,
as the patient presented a period of concussion. The energy that a
sea wave can produce can be calculated using the formula E ⫽ 1⁄8
(␳gH2), where ␳ is the density of the sea water, g is the acceleration of the gravity, and H is the height of the wave.7 With this
formula, a sea wave of 0.5 m corresponds to energy of approximately 315.4 J/m2. This energy is a crude approximation because
it would be necessary to introduce multiple modifying factors as
part of complex engineering calculations. Whether the dissection
is a result of the direct trauma of the sea wave over the anterolateral part of the neck or secondary to a sudden and forced neck
twist is not certain.
From the Neurology Department (Drs. Pego-Reigosa, López-López, VázquezLópez, Brañas-Fernández, Martínez-Vázquez, Piñeiro-Bolaño, and Cortés-

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Figure. (A and B) Axial fluid-attenuated inversion recovery and diffusion-weighted sequences showing a middle
cerebral artery territory acute ischemic stroke. (C and E)
Axial T2 (C) and T1 (E) sequences showing a hematoma
(arrows) in the wall of the right internal carotid artery.
(D) MR angiography study showing narrowing of the right
internal carotid artery.

Laiño) and Radiology Department (Dr. Armesto-Pérez), Complejo
Hospitalario Xeral-Calde, Lugo, Spain.
Received November 15, 2004. Accepted in final form February 11, 2005.
Address correspondence and reprint requests to Dr. R. Pego-Reigosa, Neurology Department, Complejo Hospitalario Xeral-Calde, C/Severo Ochoa sn,
27004 Lugo, Spain; e-mail: robustiano.pego.reigosa@sergas.es
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. Pary LF, Rodnitzky RL. Traumatic carotid artery dissection associated
with taekwondo. Neurology 2003;60:1392–1393.
3. Duncan MA, Dowd N, Rawluk D, Cunningham AJ. Traumatic bilateral
internal carotid artery dissection following airbag deployment in a patient with fibromuscular dysplasia. Br J Anaesth 2000;85:476 – 478.
4. Reddy K, Furer M, West M, Hamonic M. Carotid artery dissection secondary to seatbelt trauma: case report. J Trauma 1990;30:630 – 633.
5. Malek AM, Higashida RT, Halbach VV, et al. Patient presentation, angiographic features, and treatment of strangulation-induced bilateral
dissection of the cervical internal carotid artery. Report of three cases.
J Neurosurg 2000;92:481– 487.
6. Hughes KM, Collier B, Greene KA, Kurek S. Traumatic carotid artery
dissection: a significant incidental finding. Am Surg 2000;66:1023–1027.
7. Wright J, Colling A, Park D. Wave energy. In: Waves, tides and shallowwater processes. 2nd ed. Oxford: Butterworth-Heinemann, 1999:26 –30.

Pseudo-ulnar sensory loss in a patient from a
small cortical infarct of the postcentral knob
P. Cerrato, MD; A. Lentini, MD; C. Baima, MD; M. Grasso, MD;
C. Azzaro, MD; G. Bosco, MD; B. Bergamasco, MD; and
P. Benna, MD
A wide spectrum of sensory syndromes with different topographic
patterns have been described in patients with cerebral
infarction.1-4 The sensory abnormalities may be limited to small
areas, mimicking a radicular or trunk distribution, mainly for
lesions in sensory cortex and thalamus.
Case report. A 31-year-old man suddenly had a right arm
pain, numbness, and burning sensation on his right forearm and
hand, predominant on the ulnar side. He also reported an expressive aphasia that resolved in a few minutes. There was no history
of previous strokes. Two hours later, at admission, neurologic
examination revealed a full sensory loss for pinprick and temperature modalities restricted to the V digit, the lateral side of the IV
digit, the lateral palm, and the dorsal area of his right hand
(figure, A and B). Lemniscal sensory modalities were normal. The
hypoesthesia strictly coincided with the sensory distribution of the
ulnar nerve. Moreover, the patient had a fastidious hyperalgesia
for brush, touch, and pinprick stimuli. There was no evidence of
motor impairment; specifically, the ulnar-dependent movements
were normal. The rest of the neurologic examination was normal.
Noncontrast cerebral CT was normal, whereas a brain MRI
performed 3 days later revealed a small ischemic lesion at the
level of the midportion of the postcentral gyrus in the territory of
a parietal branch of the middle cerebral artery (see figure, C and
D). Despite the presence of a notable sensory loss, sensory and
motor nerve conduction studies of ulnar, median, and radial
nerves were normal. Somatosensory evoked potentials (SEPs)
from median and ulnar nerve at the wrist and from the V digit
were normal. MRI of the cervical spine was unrevealing.
Conventional vascular risk factors were absent. Carotid and
vertebral arteries were normal at duplex ultrasonography and
MRI angiography. Transesophageal echocardiography revealed a
large patent foramen ovale, with spontaneous flow of ⬎20 microbubbles/beat. Even though lower limb compression ultrasonography failed to reveal deep vein thrombosis and coagulation tests
were normal, we hypothesized a paradoxical embolism as stroke
mechanism. Seven days later and 4 months after discharge, the

pseudo-ulnar sensory distribution was still present; the hypoesthesia was milder if compared with that at admission, involving
mostly pinprick sensation and associated with a marked
hyperalgesia.
Discussion. Our patient presented a highly restricted sensory
loss in a distribution mimicking the ulnar nerve. At the onset,
only a transient expressive aphasia suggested the presence of a
cerebral lesion. The sensory loss was restricted to the ulnar side of
the hand; the splitting of the IV digit suggested an ulnar rather
than a radicular (C8) disease. Notably, the hypoesthesia clearly
resembled the sensory pattern observed in the compression of the
ulnar nerve at the elbow. In patients with thalamic and cortical
infarction, neurologic deficits involving both sensory and motor functions in the distribution pattern of the ulnar nerve have already been
described.1-4 Unlike several reports on pseudo-ulnar palsy,1,2,4 our patient had no impairment of the motor functions of the ulnar nerve.
The evidence of a pseudo-ulnar pinprick and temperature hypoesthesia in a patient with a postcentral infarction raises some
questions regarding the underlying pathophysiologic mechanism.
It is well known that human primary sensorimotor cortex is organized in an orderly somatotopic way (the so-called “homunculus”
described by Penfield and Boldrey).
Several studies on sensorimotor cortex with SEPs have pointed
out that cortical representations for the human hand in the postcentral gyrus have a clear somatotopic organization, from medial
superior to lateral inferior, in the following order: ulnar nerve,
median nerve, and then lip.5 The splitting of the IV digit resembling an ulnar distribution suggests that a peripheral nerve representation is already present at the cortical level.
Remarkably, our patient’s sensory loss concerned the spinothalamic modalities (pinprick and temperature sensation), while deep
lemniscal sensations were preserved. The somatosensory cortex is
organized into vertical columns, spanning all six layers from the
cortical surface to the white matter; all neurons within a single
column receive signals from the same skin area and can be elicited
by one modality only (either touch, pressure, temperature, or
pain). This happens because anatomically separate pathways convey different somatosensory modalities.6 Although each of the four
areas of the primary somatosensory cortex (3a, 3b, 1, and 2) receives inputs from all areas of the body surface, one modality
tends to dominate in each area.7 Moreover, the normality of SEPs
is in agreement with the preservation of deep lemniscal sensory
modalities, which mostly contribute to the cortical response.

Figure. Neurologic examination of a 31year-old man with right arm pain, numbness, and burning sensation on his right
forearm and hand, predominant on the
ulnar side. The examination revealed a
full sensory loss for pinprick and temperature modalities restricted to the V digit,
the lateral side of the IV digit, the lateral
palm, and the dorsal area of his right
hand (A and B). Noncontrast cerebral CT
was normal, whereas a brain MRI performed 3 days later revealed a small ischemic lesion at the level of the midportion of
the postcentral gyrus in the territory of a
parietal branch of the middle cerebral artery (C and D).

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Our case highlights the importance of suspecting cerebral ischemic lesions in patients with peripheral sensory loss when neurophysiologic investigations are normal.
From the First Division of Neurology (Drs. Cerrato, Lentini, Baima, Grasso,
Azzaro, Bosco, Bergamasco, and Benna) and Foundation S. Maugeri (Pavia)
(Dr. Bergamasco), University of Turin, Italy.
Received November 29, 2004. Accepted in final form February 14, 2005.
Address correspondence and reprint requests to Dr. P. Cerrato, First Division of
Neurology, University of Turin, Via Cherasco 15, 10126, Torino, Italy.
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Lampl Y, Gilad R, Eshel Y, et al. Strokes mimicking peripheral nerve
lesions. Clin Neurol Neurosurg 1995;95:203–207.

Seizures following reduction in
phenytoin level after orally
administered folic acid
Donald Lee Steinweg, MD, FACP; and
Michael L. Bentley, PharmD
Phenytoin reduces folate levels and may be responsible for the
development of a macrocytic anemia. This may be avoided by
prophylactic administration of folic acid to patients with seizure
who will be on long-term anticonvulsant treatment. The relationship between folate and phenytoin metabolism, however, is a dual
and interdependent one and the addition of folic acid to a stable
anticonvulsant regimen predictably lowers serum phenytoin levels.1 We report a case of recurrent seizures in a patient after the
addition of folic acid for treatment of macrocytic anemia. The
reduction in drug levels was substantial and resulted in several
seizures in a patient previously well controlled.
Case reports. A 52-year-old man was admitted to the hospital
for repair of an acute hip fracture. There was a history of cerebrovascular disease complicated by stroke, hemiparesis, and generalized tonic-clonic seizures. He had been free of seizures for the 3
years previous to admission and all outpatient phenytoin levels
were consistently between 12 and 18 ␮g/mL on a stable regiment
of 300 mg/day. He did not consume alcohol. Three weeks before
admission, his serum level was 12.4 ␮g/mL. At the time of initial
hospital evaluation, a mild macrocytic anemia was noted with
Hgb 12.1 and MCV of 104. The patient was started on five mg of
oral folate and his usual daily phenytoin dose of 300 mg/day was
continued. An interview with his caretaker confirmed that no
doses of phenytoin had been missed and the patient consumed no
alcoholic beverages. On preoperative evaluation the patient’s cardiopulmonary status was judged to be normal as was hepatic
function on laboratory testing. The only other new medication
administered was morphine for pain control. The following day he
had a grand mal seizure with full recovery in 45 minutes. A
phenytoin level was 4.5 ␮g/mL. He was given 500 mg of fosphenytoin with continued oral dosing of 300 mg/day. His level 18 hours
later was essentially unchanged (4.8 ␮g/mL) and he had another
generalized tonic-clonic seizure. One gram of fosphenytoin was
then given and the folic acid dose was reduced to 1 mg per day. All
further seizure activity was suppressed and phenytoin levels were
measured at 17.6 ␮g/mL the following day. A subsequent predischarge trough level 24 hours later was 11.3 ␮g/mL on 1 mg of folic
acid and 300 mg of phenytoin per day.
Discussion. Folate has been shown to be a coenzyme necessary for red blood cell development, normal gastrointestinal integrity, and maintenance of normal neurologic function. Proposed
mechanisms by which phenytoin causes a decrease in serum and
RBC folate levels include decreased gastrointestinal absorption of
folate with impairment of folate transport in tissues2 and depletion due to phenytoin induced increase in hepatic metabolism.3
New, lowered, steady state folate levels occur within 2 to 3 weeks
of the initiation of phenytoin.
The impact of adding folic acid to a stable phenytoin regimen
in an effort to correct folate deficiency is often underestimated. A

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2. Kim JS. Predominant involvement of a particular group of fingers due to
small, cortical infarction. Neurology 2001;56:1677–1682.
3. Bassetti C, Bogousslavsky J, Regli F. Sensory syndromes in parietal
stroke. Neurology 1993;43:1942–1949.
4. Phan TG, Evans BA, Huston J. Pseudoulnar palsy from a small infarct of
the precentral knob. Neurology 2000;54:2185.
5. Baumgartner C, Barth DS, Levesque MF, et al. Human hand and lip
sensory motor cortex as studied on electrocorticography. Electroencephalogr Clin Neurophysiol 1992;84:115–126.
6. Kaas JH, Nelson RJ, Sur M, et al. Organization of somatosensory cortex
in primates. In: Schmitt FO, Worden FG, Adelmann G, Dennis SG, eds.
The organization of the cerebral cortex: proceedings of Neurosciences
Research Program Colloquium. Cambridge, MA: MIT Press, 1981:237–
261.
7. Sur M, Merzenich M, Kaas JH. Modular distribution of neurons with
slowly adapting and rapidly adacting responses in area 3b of somatosensory cortex in monkeys. J Neurophysiol 1984;51:724 –744.

number of studies have investigated the effect of folic acid on
serum phenytoin concentrations. The mean decrease in total serum phenytoin after the addition of 1 mg of folic acid in four
folate-deficient men aged 30 to 43 years was 20.6% on day 15 in
one study4 and in a second study of seven folate-deficient men,
there was a similar 22.6% drop in phenytoin levels.5 Literature
review suggests that the effect of 5 mg of oral folic acid (the dose
our patient received) will result in a 39.1% drop in drug levels.6
Pharmacokinetic studies of this interaction strongly suggest that
folic acid is a cofactor in the metabolism of phenytoin. While the
effect that folic acid has on the nonlinear and dose-dependent
pharmacokinetics of phenytoin is cumbersome to delineate, several authors have demonstrated significant changes in the
Michaelis–Menton parameter (Km) for phenytoin when folate levels were manipulated.5,7 Higher levels of folate appear to increase
the affinity of metabolizing enzymes thus greatly increasing the
efficiency of phenytoin degradation.
Our case is a vivid reminder that the relationship between folic
acid and phenytoin is a dual and interdependent one. The use of
folic acid in clinical medicine has increased dramatically in recent
years, underscoring the need to disseminate this pharmacologic
relationship. Clinicians adding folic acid to the regimens of folate
deficient patients should make anticonvulsant adjustments that
anticipate significant reductions in phenytoin concentrations and
potential loss of seizure control.
From the School of Medicine (Dr. Steinweg), University of Virginia, Charlottesville; Roanoke-Salem Internal Medicine Program (Dr. Steinweg); and
Virginia Commonwealth University School of Pharmacy (Dr. Bentley),
Richmond.
Received December 21, 2004. Accepted in final form February 26, 2005.
Address correspondence and reprint requests to Dr. Donald L. Steinweg,
Carilion Roanoke Memorial Hospital, P.O. Box 13367, Roanoke, VA 24033;
e-mail: Dsteinweg@carilion.com
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Seligmann H, Potasman I, Weller B, Schwartz M, Prokocimer M.
Phenytoin-folic acid interaction: a lesson to be learned. Clin Neuropharmacol 1999;22:268 –272.
2. Benn A, Swan CH, Cooke WT, Blair JA, Matty AJ, Smith ME. Effect of
intraluminal pH on the absorption of pteroylmonoglutamic acid. BMJ
1971;1:148 –150.
3. Maxwell JD, Hunter J, Stewart DA, Ardeman S, Williams R. Folate
deficiency after anticonvulsant drugs: an effect of hepatic enzyme induction. BMJ 1972;1:297–299.
4. Berg MJ, Fisher LJ, Rivey MP, Vern BA, Lantz RK, Schottelius DD.
Phenytoin and folic acid interaction: a preliminary report. Ther Drug
Monitor 1983;5:389 –394.
5. Berg MJ, Ebert BE, Rivey MP, Schottelius DD. Utilization of Km for
phenytoin dosage after folate addition to patient regimen. Ther Drug
Monit 1987;9:304 –305.
6. Inoue F, Kolabinski I. Possible interaction between phenytoin therapy
and folate supplement: two case reports. Can J Hosp Pharm 1986;39:16 –
18.
7. Berg MJ, Rivey MP, Vern BA, Fischer LJ, Schottelius DD. Phenytoin
and folic acid: individualized drug-drug interaction. Ther Drug Monit
1983;5:395–399.

Familial polyneuropathy with anti-myelinassociated glycoprotein antibodies
J. Srinivasan, MBBS, PhD; V.G. Tseng, MD; D. Yang, BS;
B.T. Harris, MD; H.R. Jones, MD; and E.W. Stommel, MD
We describe the occurrence of the anti-myelin-associated glycoprotein (anti-MAG) syndrome, a well-recognized variant of chronic
inflammatory demyelinating polyneuropathy (CIDP) with distinct
clinical and electrophysiologic characteristics, in two brothers.
Case 1. A 70-year-old man presented with symmetric numbness distal to his knees, followed by progressive imbalance and
gait unsteadiness that developed over 2 years. His similarly affected brother is described below (Case 2); there was no other
relevant family history. On examination he had mild distal weakness in both lower limbs and symmetric vibration and proprioceptive loss distally in all four limbs. Muscle stretch reflexes were
absent. Gait was severely ataxic and Romberg’s sign was present.
Nerve conduction studies revealed a severe demyelinating polyneuropathy with disproportionate distal slowing, prolongation of F
waves without evidence of conduction block, and met criteria for
CIDP.1 Immunoglobulin M (IgM) kappa monoclonal gammopathy
was identified; IgM was 235 mg/dL (normal, 50 to 200 mg/dL) of
which 50% to 90% was monoclonal and anti-MAG reactivity was
positive at a titer of 35 U/L (normal, ⬍16 U/mL; Focus Technologies Inc., Cypress, CA). CSF analysis revealed an elevated protein
of 92 mg/dL (normal, ⬍45 mg/dL) with no cells. Genetic tests for
hereditary motor sensory neuropathy type 1A and 1B were negative as was connexin 32 DNA sequencing (Athena Diagnostics,
Worcester, MA). The patient received plasma exchange and IV
immunoglobulin with no sustained benefit. Rituximab (375 mg/m2
weekly for 4 weeks) led to an improvement of his gait: the modified Rankin disability scale improved from 4 (moderate-severe
disability) to 3 (moderate disability). The patient has received
rituximab (375 mg/m2 weekly for 4 weeks) at 6 monthly intervals
for 2 years.
Case 2. The 72-year-old older brother of the first patient developed numbness and mild bilateral lower-limb weakness over 2
years. On examination, he had bilateral foot dorsiflexor weakness
with prominent vibration and proprioceptive loss in the distal
lower limbs. Muscle stretch reflexes were absent. His gait was
wide-based and ataxic and Romberg’s sign was present. He had
mild disability, graded on the modified Rankin Scale as 2. EMG
revealed a severe demyelinating polyneuropathy with disproportionate distal slowing, prolongation of F waves without evidence of
conduction block, and met criteria for CIDP.1 An IgM kappa monoclonal gammopathy was identified with total IgM of 638 mg/dL
(normal range: 40 to 230 mg/dL). Anti-MAG reactivity was positive at a titer of 1:25,600 (normal ⬍1,600, Athena Diagnostics).
CSF protein was 61 mg/dL (normal, ⬍45 mg/dL) with no cells.
Genetic tests for hereditary motor sensory neuropathy type 1A and
1B and connexin 32 DNA sequencing were negative (Athena Diagnostics). A sural nerve biopsy demonstrated demyelinating and axonal features with focal linear IgM deposition (figure). The patient
had no benefit with IVIg and received rituximab (375 mg/m2 once
each week for 4 weeks) with stabilization of symptoms.
Discussion. This is a report of two siblings with clinical and
electrophysiologic features typical for an anti-MAG-associated demyelinating neuropathy. Although there are three reports of the
familial association of monoclonal gammopathy and polyneuropathy, none was associated with the presence of anti-MAG
antibodies.2-4 Genetic factors may also be operative in the development of monoclonal gammopathy and multiple myeloma.5 Monoclonal gammopathies of unknown significance are identified in 3%
of individuals over age 70 years and occur in 10% of patients with
peripheral neuropathies of unknown etiology, although the association may be fortuitous.6 Up to 50% of patients with IgM monoclonal gammopathies develop polyneuropathy.6 Anti-MAG antibodies
occur in patients with IgM kappa monoclonal gammopathy, although there are rare reports of the occurrence of anti-MAG antibodies without detectable monoclonal gammopathy. These
antibodies are thought to have a pathophysiologic role; they intercalate within the layers of myelin leading to widening of lamellae
and architectural derangement, resulting in demyelinating
polyneuropathy.6
Patients with CIDP who have monoclonal gammopathy (CIDPMGUS) are distinct from classic CIDP.6 CIDP-MGUS patients
tend to be males over 60 years, with a progressive, sensory-

Figure. (A) Immunofluorescence staining specific for human immunoglobulin G displays diffuse, nonspecific pattern. (B) Immunoglobulin M-specific immunofluorescence
staining displays focal, linear pattern, which probably
represents staining of the few remaining myelinated axons
of this sural nerve biopsy. (Bar measures 100 ␮m.)
predominant demyelinating polyneuropathy.6 Immunomodulatory
therapies are characteristically unsuccessful in these patients.6
Patients with anti-MAG antibodies and demyelinating neuropathy are a select subset of the CIDP-MGUS. On electrodiagnostic
studies they have disproportionate distal slowing on nerve conduction studies. The anti-MAG syndrome does not respond to standard immunomodulating therapies including plasma exchange, IV
immunoglobulin, corticosteroids, or cyclophosphamide.6 Rituximab, a monoclonal antibody directed against the B cell surface
membrane marker CD20, is well tolerated and early reports suggest that this may be a promising agent in the anti-MAG neuropathy syndrome; our experience to date is similar.7 We recommend
evaluation for monoclonal gammopathy and anti-MAG antibodies
in symptomatic relatives of patients with acquired demyelinating
polyneuropathy.
From the Department of Neurology (Drs. Srinivasan and Jones, and D.
Yang), Lahey Clinic, Burlington, MA; and Departments of Neurology (Drs.
Tseng and Stommel) and Pathology (Dr. Harris), Dartmouth-Hitchcock
Medical Center, Lebanon, NH.
Received December 16, 2004. Accepted in final form February 17, 2005.
Address correspondence and reprint requests to Dr. Jayashri Srinivasan,
Department of Neurology, Lahey Clinic 41, Mall Road, Burlington, MA
01805; e-mail: Jayashri.Srinivasan@lahey.org
Copyright © 2005 by AAN Enterprises, Inc.
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References
1. Ad Hoc Subcommittee of the American Academy of Neurology AIDS
Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991;41:617– 618.
2. Busis NA, Halperin JJ, Stefansson K, et al. Peripheral neuropathy, high
serum IgM, and paraproteinemia in mother and son. Neurology 1985;35:
679 – 683.
3. Jensen TS, Schroder HD, Jonsson V, et al. IgM monoclonal gammopathy
and neuropathy in two siblings. J Neurol Neurosurg Psychiatry 1988;51:
1308 –1315.

Hemiplegic ALS: Mills syndrome
Yusuf A. Rajabally, MD; Majed Hbahbih, MBBS; and
Richard J. Abbott, MD
Originally described in 1900,1 progressive hemiplegia, also known
as Mills syndrome, is a rare motor neuron disease. However, the
existence of this entity has been subject to debate.2,3 A more recent
report suggested that it could represent a variant of primary lateral sclerosis (PLS).2 We describe a patient with progressive hemiplegia with electrophysiologically confirmed and exclusively
unilateral lower motor neuron involvement who was later also
found to have Waldenstrom macroglobulinemia (WM).
Case report. A 69-year-old man presented with a 12-year history of very slowly progressive right lower limb weakness and
wasting. Ipsilateral upper limb involvement started about 5 years
after onset. He denied any sensory symptoms or sphincter involvement. His past medical history was unremarkable, as was his
family history. On examination, he presented distal (Medical Research Council [MRC] grade 2 to 3) more than proximal (MRC
grade 4) right lower limb weakness affecting all muscle groups.
The right upper limb was also weak, again more distally (MRC
grade 3) than proximally (MRC grade 4). Tone was moderately
increased on the right. Reflexes were pathologically brisk in all
four limbs, more on the right. Hoffmann sign was present bilaterally. Plantar responses were flexor. There was severe atrophy
without visible fasciculations mainly of the distal muscles of right
upper and lower limbs. Sensation was entirely normal bilaterally
to all modalities, including vibration and joint position. Cranial
nerve functions were unimpaired, coordination and vision were
normal. Routine blood investigations (full blood count, inflammatory markers, electrolytes, renal function, liver enzymes, calcium,
creatine kinase, thyroid function) revealed a moderately raised
white cell count (11,300/␮L). Anti-GM1 antibodies were negative.
Serum and urinary lead levels were within normal limits as was
parathormone level. Serum protein electrophoresis revealed a
raised IgM level of 16.5 g/L with an IgM lambda monoclonal band
of 10.3 g/L. Bone marrow aspirate and biopsy showed an increase
of up to 70% of the lymphocyte population and was consistent with
a diagnosis of WM. Skeletal survey was normal. CSF examination

4. Manschot SM, Notermans NC, van den Berg LH, Verschuuren JJ, Lokhorst HM. Three families with polyneuropathy associated with monoclonal gammopathy. Arch Neurol 2000;57:740 –742.
5. Grosbois B, Jego P, Attal M, et al. Familial multiple myeloma: report of
fifteen families. Br J Haematol 1999;105:768 –770.
6. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia.
N Engl J Med 1998;338:1601–1607.
7. Pestronk A, Florence J, Miller T, Choksi R, Al-Lozi MT, Levine TD.
Treatment of IgM antibody associated polyneuropathies using rituximab.
J Neurol Neurosurg Psychiatry 2003;74:485– 489.

showed a normal protein of 0.33 g/L, and normal cytology. Motor
and sensory nerve conduction studies showed no significant abnormality (table). Needle EMG showed, exclusively in right-sided
muscles, a combination of abundant spontaneous fasciculations,
fibrillation potentials, and positive sharp waves in the upper and
lower limb, proximal and distal muscles (right first dorsal interosseous, deltoid, tibialis anterior, and quadriceps femoris), and
large, long duration, polyphasic potentials with reduced recruitment on voluntary contraction. Acute denervation was not detected in the same four muscles investigated on the left side, with
only rare, isolated fasciculations being recorded. Repeat nerve
conductions were refused by the patient, who, however, agreed to
undergo a second EMG 6 months later. No significant changes
were observed, with persistent, exclusively unilateral signs of denervation being present in all tested right-sided muscles. A brain
MRI scan showed mild periventricular ischemic changes and a
cervical MRI was normal. A diagnosis of clinically probable ALS
according to the El Escorial criteria4 was made.
Discussion. Since Mills’ original description,1 few additional
cases have been reported.2 The scarcity of reports and lack of
pathologic data raised doubt about the authenticity of this syndrome, since all the published cases except for two2 dated back to
times when it was not possible to exclude definitely a structural
abnormality as the underlying cause.2,3 WM has occasionally been
reported in association with anterior horn cell disease, although
whether the gammopathy plays any role in the pathophysiology of
motor neuron involvement is unclear.5 Because it was diagnosed
12 years after the onset of the neurologic problems, and having
remained asymptomatic for years as can be the case,6 the implication here of the lymphoproliferative disease in relation to the
motor neuron disorder remains uncertain. A common cause explaining both disorders remains plausible.
Few if any similar cases have been reported since 1994,2 indicating the rarity of idiopathic progressive hemiplegic syndromes.
However, the two previous cases had PLS rather than ALS and
the authors suggested Mills syndrome could be considered a PLS
variant.2 Mills had initially described eight cases of a very slowly
advancing form of hemiplegia starting in the lower limb and then
spreading to the ipsilateral upper limb.1,2 Reports through the

Table Nerve conduction study results

Motor nerve
Right median-recorded
APB

Right common
peroneal-recorded
EDB

Left common peronealrecorded EDB

Latency, ms

Amplitude, mV

Amplitude,
%

Wrist

3.9 (normal ⬍4)

7.3 (normal ⬎5)

100

Elbow

8.50

6.0

81.5

Ankle

5.25 (normal ⬍6.5)

4.0

100

Fibular neck 13.60

3.5

86.6

Ankle

4.60

5.2

100

Fibular neck 12.55

3.3

63.4

Site

Velocity, m/s

Minimum F-wave
latency, ms
25.60 (normal ⬍30)

58.2 (normal ⬎48)
61.65 (normal ⬍55)

40.1 (normal ⬎44)
56.80
42.8

Sensory conduction studies: right median potential: 11.3 ␮V (normal ⬎10), velocity: 44.0 m/s (normal ⬎40); right sural potential: 6.9
␮V (normal ⬎5), velocity: 41.6 m/s (normal ⬎38).
APB ⫽ abductor pollicis brevis; EDB ⫽ extensor digitorum brevis.
1984

NEUROLOGY 64

June (1 of 2) 2005

early 1950s described cases with very slow progression, ascending
weakness, pyramidal tract signs, amyotrophy without fasciculations, and occasional facial weakness, with rare sensory disturbances. A family history of similar problems was rarely reported.
Most cases had persistent unilaterality after 15 years, although
spread to the contralateral side was reported in a third.
The features present in our patient with ALS resemble those of
these earlier cases, as did those of the previously described two
patients who had PLS.2 This report suggests that progressive
hemiplegia or what has been known as Mills syndrome can correspond not only to hemiplegic PLS, but also in some cases to hemiplegic ALS. The natural course of this mild unilateral motor
neuron disease variant seems, in either case, identical, suggesting
a different pathophysiologic basis for neuronal death in this form
of the condition.
From the Department of Neurology, University Hospitals of Leicester, Royal
Infirmary Leicester, UK.
Received December 21, 2004. Accepted in final form March 1, 2005.
Address correspondence and reprint requests to Dr. Y.A. Rajabally, Department of Neurology, University Hospitals of Leicester, Royal Infirmary, Leicester LE1 5WW, UK; e-mail: yusuf.rajabally@uhl-tr.nhs.uk

Copyright © 2005 by AAN Enterprises, Inc.

References
1. Mills CK. A case of unilateral progressive ascending paralysis probably
representing a new form of degenerative disease. J Nerv Ment Dis 1900;
27:195–200.
2. Gastaut JL, Bartolomei F. Mills’ syndrome: ascending (or descending)
progressive hemiplegia: a hemiplegic form of primary lateral sclerosis?
J Neurol Neurosurg Psychiatry 1994;57:1280 –1281.
3. Malin JP, Poburski R, Reusche E. Clinical variants of amyotrophic lateral sclerosis: hemiplegic type of ALS and Mills syndrome. A critical
review. Fortschr Neurol Psychiatry 1986;54:101–105.
4. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis
of the World Federation of Neurology Research Group on Neuromuscular
Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. El Escorial World Federation of Neurology
criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci
1994;124:96 –107.
5. Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders
and motor neuron disease: an update. Neurology 1997;48:1671–1678.
6. Alexanian R, Weber D, Delasalle K, Cabanillas F, Dimopoulos M.
Asymptomatic Waldenstrom’s macroglobulinaemia. Semin Oncol 2003;
30:206 –210.

June (1 of 2) 2005

NEUROLOGY 64

1985

Sea wave−induced internal carotid artery dissection
R. Pego-Reigosa, S. López-López, M. E. Vázquez-López, et al.
Neurology 2005;64;1980
DOI 10.1212/01.WNL.0000163855.78628.42
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