Diltiazem-induced myoclonus
`
`To the Editor: In the report by Vadlamudi and Wijdicks on
`verapamil-induced myoclonus,1 the authors omit diltiazem from
`their table of drugs that cause myoclonus. Diltiazem has been
`found to cause reversible myoclonus, even at therapeutic doses.2
`Although their patients overdosed on a calcium-channel blocker, it
`should be stressed that this class of medications can cause myoc-
`lonus even at therapeutic doses.
`Joseph S. Jeret, MD, Rockville Centre, NY
`
`Reply from the Authors: No table pretends to be all inclusive,
`but we assume that if myoclonus is seen in one calcium-channel
`
`The pulvinar sign and diagnosis of
`Creutzfeldt-Jakob disease
`
`To the Editor: Haïk et al. present a case report of a patient with
`histologically confirmed sporadic Creutzfeldt-Jakob disease
`(sCJD) with bilateral increased signal in the pulvinar of the thal-
`amus.1 We felt it important to clarify recent changes in the defini-
`tion of the pulvinar sign to avoid difficulties in future diagnosis of
`variant CJD (vCJD) using MRI.
`The presence of pulvinar hyperintensity was originally de-
`scribed as a characteristic feature of vCJD by Sellar et al.2 in
`1997, and the high sensitivity and specificity of this sign were
`subsequently documented by our group.3 Clinical criteria for a
`diagnosis of vCJD were formulated that incorporated these MRI
`findings with diagnostic changes defined as bilateral pulvinar
`high signal on MRI scan.4 It has been recognized that this defini-
`tion was ambiguous, as it was unclear with which structure the
`degree of pulvinar hyperintensity was compared.
`Recently, a more specific definition of the pulvinar sign has
`been developed and included in the recently published World
`Health Organization (WHO) revised case definition of vCJD.5 The
`new definition of the pulvinar sign in vCJD is bilateral symmetri-
`cal pulvinar high signal relative to the signal intensity of other
`deep grey matter nuclei and cortical grey matter. This definition
`emphasizes that, for the sign to be considered positive, the highest
`signal of grey matter is within the pulvinar of the thalamus in
`vCJD; this does not exclude some increase in signal in other grey
`matter structures. Recent analysis by our group of MRI scans of
`patients with definite vCJD has shown that the sensitivity of the
`pulvinar sign for a diagnosis of vCJD remains very high and in fact
`has increased with the wider use of fluid-attenuated inversion recov-
`ery imaging and with improvements of MRI scanner technology.
`There is considerable overlap in the appearances of grey mat-
`ter structures in different forms of CJD. However, to date the
`pulvinar sign (as defined in the WHO criteria) remains a robust,
`sensitive, and highly specific noninvasive diagnostic sign of vCJD
`that has not been reported in other forms of CJD. The imaging
`appearances correlate with extensive neuronal loss and gliosis
`within the pulvinar on neuropathologic studies,3 changes that
`have not been reported in other forms of CJD.
`We have encountered several cases where a false-positive diag-
`nosis of vCJD has been suggested by radiologists and clinicians
`that are not experienced in the diagnosis of this form of the dis-
`ease. We hope the improved definition of the pulvinar sign of
`vCJD will reduce the number of these cases and are happy to
`provide a second opinion of MRI scans in which the diagnosis is
`
`Correspondence
`blocker, it likely will be seen in other calcium-channel blockers as
`well. Dr. Jeret’s observation in two patients with episodic myoclo-
`nus but without evidence of toxicity is quite helpful.
`
`Eelco F.M. Wijdicks, MD, Rochester, MN
`
`Copyright © 2002 by AAN Enterprises, Inc.
`
`References
`1. Vadlamudi L, Wijdicks EFM. Multifocal myoclonus due to verapamil
`overdose. Neurology 2002;58:984–985.
`2. Jeret JS, Somasundaram M, Asaikar S. Diltiazem-induced myoclonus:
`report of two cases. NY State J Med 1992;92:447–448.
`
`suspected clinically but interpretation of the scan is considered
`difficult.
`D.M. Summers, MD, D.A. Collie, MD, R.J. Sellar, MD,
`M. Zeidler, MD, R. Knight, MD, R.G. Will, MD,
`J.W. Ironside, MD, Edinburgh, Scotland, UK
`
`Reply from the Authors: We thank Summers et al. for their
`useful comments on our report about the specificity of the pulvi-
`nar sign for the diagnosis of vCJD versus sCJD. They emphasize
`the importance of the recent revision of the vCJD case definition
`illustrated by the case that we reported. In this sCJD case, there
`was a confusing clinical course, neuropathologic lesions, and in-
`creased signal on MRI in the pulvinar. However, the signal of the
`putamen was higher than the pulvinar signal in a T2-weighted
`sequence and diffusion-weighted images. Thus, the pulvinar high
`signal in this case could not be considered as a genuine pulvinar
`sign.3,5 We agree that the first definition of MRI findings in the
`clinical criteria for the diagnosis of vCJD4 was ambiguous, as
`illustrated by our report, and that MRI pattern of vCJD and sCJD
`can share signal abnormalities, especially in the deep grey matter.
`Therefore, it was necessary to clarify the MRI criteria for the
`diagnosis of vCJD. A more precise definition is now available5 and
`in agreement with our conclusion.1 We hope that our report and
`the comments of Summers et al. can facilitate the difficult MRI
`approach of vCJD diagnosis.
`S. Haïk, MD, J.P. Brandel, MD, C. Oppenheim, MD,
`V. Sazdovitch, MD, D. Dormont, MD, J.J. Hauw, MD,
`C. Marsault, MD, Paris, France
`
`Copyright © 2002 by AAN Enterprises, Inc.
`References
`1. Haïk S, Brandel JP, Oppenheim C, Sazdovitch V, et al. Sporadic CJD
`clinically mimicking variant CJD with bilateral increased signal in the
`pulvinar. Neurology 2002;58:148–149.
`2. Sellar RJ, Will RG, Zeidler M. 1997. MR imaging of new variant
`Creutzfeldt-Jakob disease: the pulvinar sign. Neuroradiology 1997;39:
`S53.
`3. Zeidler M, Sellar RJ, Collie DA, et al. The pulvinar sign on magnetic
`resonance imaging in variant Creutzfeldt-Jakob disease. Lancet 2000;
`355:1412–1418.
`4. Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant
`Creutzfeldt-Jakob disease. Ann Neurol 2000;47:575–582.
`5. The revision of the variant Creutzfeldt-Jakob (vCJD) case definition.
`Report of a WHO Consultation. Edinburgh, United Kingdom. WHO/
`CDS/CSR/EPH/2001.
`
`Economy class stroke syndrome
`
`To the Editor: Isayev et al.1 describe three cases of ischemic
`stroke in young adults that occurred during or after air travel. All
`patients were diagnosed with persistent foramen ovale (PFO), and
`no other plausible cause of stroke could be found, suggesting the
`existence of an “economy class stroke syndrome.” To underscore
`
`962
`
`NEUROLOGY 59 September (2 of 2) 2002
`
`the importance of their report, we would like to add three very
`similar patients (aged 21, 63, and 64 years) with otherwise unex-
`plained ischemic strokes that occurred during long-distance air
`travel (⬎ 9000 km in each case) who were admitted to our depart-
`ment within the past year. All patients developed their symptoms
`toward the end of their flights, one patient immediately after a
`prolonged defecation with repeated Valsalva maneuvers. All in-
`
`MYLAN - EXHIBIT 1012
`
`

`

`farcts appeared embolic upon brain imaging. They were located in
`the right middle cerebral artery territory in one patient and in the
`posterior thalamus with transient “top of the basilar” syndrome in
`another. The third patient had multiple embolic cerebral infarctions
`accompanied by fulminant pulmonary embolism. The latter patient
`carried a homozygote prothrombin gene G20210a mutation and sub-
`sequently died due to cerebral herniation. The other two patients
`recovered with no or minimal residual deficits. All patients had a
`PFO as demonstrated by transesophageal echocardiography; one pa-
`tient had an additional intraseptal aneurysm. Similar to the patients
`reported by Isayev et al.,1 lower limb venous Doppler performed
`within 1 to 3 days after the events was negative in all three cases, as
`were their extracranial and intracranial Doppler/duplex examina-
`tions, ECG-holter recordings, and all other coagulation studies (anti-
`thrombin, factor V Leiden mutation, anticardiolipin antibodies, lupus
`anticoagulant, proteins C and S). Although two of our patients were
`already in their 60s, none showed evidence of atherosclerosis or other
`cardiovascular risk factors.
`Of course, owing to the worldwide increase in air travel, more
`people will suffer a stroke in flight by mere chance. Nevertheless,
`we also assume that embolic strokes during or due to long-
`distance air travel have been underreported in the literature, but
`one more patient was reported a few years ago in a French jour-
`nal.2 Until more systematic investigations become available, ische-
`mic stroke should be included in the list of potential complications
`of long-distance air travel, especially in the presence of PFO.
`
`Christian Foerch, Kirn R. Kessler, Helmuth Steinmetz, and
`Matthias Sitzer, Frankfurt am Main, Germany
`
`Reply from the Authors: We thank Foerch et al. for their comment
`and for bringing to our attention the article by Masson et al.2 Similar
`to the three cases we reported, the strokes reported by Foerch et al.,
`appear to be related to prolonged air travel. Their cases were related
`to flights of about 10 hours or more. Although longer duration flights
`have a higher risk of pulmonary embolism and probably also of
`stroke, our cases suggest that stroke can be related to shorter dura-
`tion flights as well. An important similarity to our experience is that
`the three cases reported by Foerch et al. were collected from a single
`center within a very short period of time. This suggests that the
`“economy class” stroke syndrome is probably not rare, particularly
`with current high volumes of intercontinental flights.
`
`Richard K. Chan, MBBS, FRCP (Edin), Patrick Pullicino, MD,
`Ph.D, Newark, NJ
`
`Copyright © 2002 by AAN Enterprises, Inc.
`
`References
`1. Isayev Y, Chan RKT, Pullicino PM. “Economy class” stroke syndrome.
`Neurology 2002;58:960–961.
`2. Masson C, Perrotte P, Mariescu A. Cerebral ischemic complication after
`transatlantic flight. Presse Med 1997;26:269–270.
`
`Manometry combined with cervical puncture in
`idiopathic intracranial hypertension
`
`To the Editor: We agree with King et al.1 that there is a relation-
`ship between intracranial pressure and sinus venous pressure. We
`do, however, have concerns over the authors’ conclusion that in-
`creased cerebral venous pressure found in most patients with
`isolated intracranial hypertension (IIH) is due to a functional
`obstruction (collapse of the walls) of the transverse sinuses (TS)
`by raised intracranial pressure and not due to a primary obstruc-
`tive process in the TS.
`We recently demonstrated on MR venography (MRV) that a
`number of subjects with IIH with or without papilledema had
`flowing abnormalities of both transverse sinuses, which is highly
`suggestive of cerebral venous thrombosis.2,3 It is noteworthy that
`the flowing abnormalities seen on MRV in IIH occurred mainly in
`the distal portion of the TS.2,3 This observation was confirmed by
`King et al.,1 who showed a pressure gradient between the proxi-
`mal and distal part of the TS in patients with IIH. These findings
`suggest there must be some anatomic reason that makes the dis-
`tal part of the transverse sinus the preferential site for developing
`an obstructive process. Because arachnoidal granulations typi-
`cally occur in the distal portion of the TS,4 it is reasonable to
`hypothesize that in some individuals large arachnoid granulations
`could produce relative luminal compromise and lead to a dis-
`turbed flow with a pressure gradient or an increased risk of ve-
`nous thrombosis. Taken together, these data indicate that
`obstruction of the distal portion of one or both TS, which occurs in
`many patients with IIH,2,3,5 is probably due to an intraluminal
`process (prominent arachnoidal granulations, thrombus forming
`on arachnoidal granulations, or venous thrombosis) rather than to
`an extrinsic cause (i.e., raised intracranial pressure), which
`should collapse the walls of the entire TS and not just the walls of
`the distal portion. Consistent with this hypothesis, a recent paper5
`described a patient with IIH who showed, on venography and
`manometry, a partial obstruction of the distal portion of both TS
`with raised pressure proximal to the obstruction. Dilatation of one
`of the transverse sinuses with a stent reduced both the pressure
`gradient and CSF opening pressure with striking symptomatic
`improvement, suggesting a causal relationship between venous
`outflow obstruction and IIH. Finally, we agree with King et al.1
`that raised intracranial pressure could make the obstruction
`worse by collapsing the walls of the sinus, thus further exacerbat-
`ing both venous hypertension and CSF pressure.
`
`A. Quattrone, MD, F. Bono, MD, K. Pardatscher, MD,
`Catanzaro, Italy
`
`To the Editor: King et al.1 reported the results of cerebral venous
`sinus manometry and cervical puncture in IIH. They reported cere-
`bral venous sinus hypertension in the superior sagittal and proximal
`TS that was reversed by reducing intracranial pressure. They con-
`cluded that the elevated intracranial pressure and not the other way
`around caused compression of the dural walls of the TS. Lee and
`Brazis6 previously performed a prospective study to evaluate for the
`presence or absence of dural sinus thrombosis using MRI and MRV
`of the brain in 22 consecutive young, overweight women with typical
`IIH. None of the 22 MRI and MRV studies showed venous sinus
`thrombosis, and they concluded that MRV might not add signifi-
`cantly to the evaluation of typical IIH. I still order cranial MRI/MRV,
`however, in atypical IIH cases (e.g., male, thin, or elderly patients).
`I have been impressed by the number of MRV studies in IIH
`that have shown findings that we have in the past interpreted as
`being suggestive of venous sinus stenosis or flow-related turbu-
`lence at the level of the distal transverse sinus. Some of these
`patients underwent standard catheter venography, and a few
`were even considered for possible stenting. Thus, the MRV studies
`in these patients actually confounded the evaluation of their IIH.
`My questions for the authors are as follows:
`1. Did any of their patients undergo MRV in addition to cranial
`MRI, and if so did these MRV show anything that might have
`been misinterpreted as venous sinus thrombosis or obstruction
`at the distal TS?
`2. Do the authors believe that performing an MRV in typical IIH
`might be misleading in the management of typical IIH in cases
`with flow-related abnormalities (but not true obstruction) at
`the distal TS?
`3. Would pre- and postlumbar puncture MRV be able to demon-
`strate the reversibility of flow-related signal abnormalities at
`this level?
`This work is fascinating, and I commend the authors for their
`efforts in this area.
`Andrew G. Lee, MD, Iowa City, IA
`
`To the Editor: We disagree with the conclusions of King et al.1
`and with the enthusiasm with which they were greeted in the
`accompanying editorial.7 We also have found pressure gradients
`across stenoses in the lateral sinuses in patients with apparent
`IIH. Furthermore we have dilated one of these stenoses with a
`stent, thereby reducing the pressure gradient, which resulted in
`almost complete resolution of symptoms.5 Hence, we strongly sup-
`port the original King et al. hypothesis that venous outflow ob-
`struction is the primary cause of IIH, at least in some cases.
`There is no doubt that the TS may collapse in response to raised
`intracranial pressure and that in this situation pressure gradients
`
`September (2 of 2) 2002 NEUROLOGY 59 963
`
`

`

`will be detected along them. Moreover, these gradients will resolve if
`intracranial pressure is reduced.8 Equally, narrowing or occlusion of
`the intracranial venous sinuses can cause that raised intracranial
`pressure. With reference to this paper, it is important to reiterate
`that raised intracranial pressure in patients with unequivocal cere-
`bral venous thrombosis is relieved by CSF diversion.1 Where there is
`stenosis or thrombosis of the sagittal or transverse sinuses, a second-
`ary rise in cerebral venous pressure must be accompanied by an even
`greater rise in CSF pressure if CSF absorption is to continue. Where
`cerebral venous pressure or intracranial pressure is raised, there will
`be an autoregulatory vasodilatation to maintain cerebral blood flow
`constant in the otherwise healthy brain. If CSF is diverted and intra-
`cranial pressure reduced, such cerebral vasodilatation will reverse,
`very likely with a fall in cerebral venous pressure.9 A fall in cerebral
`venous pressure in response to a withdrawal of CSF, therefore, does
`not exclude venous outflow obstruction as the cause of raised intra-
`cranial pressure.
`Another question, not explored, is any secondary effect of raised
`intracranial pressure on the venous sinuses when intracranial hy-
`pertension is due to venous sinus obstructions, especially at points
`where the sinuses are known to be compressible. In the cranial
`cavity the raised intracranial pressure itself will act as a force on the
`sinus wall, resisting any expansion that might mitigate the obstruct-
`ing lesion. Reducing intracranial pressure by removing CSF would
`alter this transmural gradient and might allow the sinus to expand.
`If this expansion were sufficient, then the intrasinus pressure gradi-
`ents across the stenotic lesions would fall acutely, in the manner
`recorded by King et al.1 One can speculate further that after this
`acute response equilibrium will be restored at a rate depending on
`the degree of “primary” sinus stenosis and the compliance of the
`sinus wall under strain from rising intracranial pressure—parallel-
`ing the clinical effects of CSF withdrawal.
`Whatever the mechanism operating here, we suggest that if
`pressure gradients along the TS were always secondary to IIH,
`then dilating one of these stenotic areas would not have caused
`the intracranial pressure to fall nor effected the clinical improve-
`ment we observed in our reported case. We applaud the pioneer-
`ing observations of King et al. from 199510 but are anxious that a
`misinterpretation of their most recent results, unquestioned in
`your editorial, will stall a line of research that may yet revolution-
`ize our understanding of this condition.
`J. Nicholas, P. Higgins, John D. Pickard, Cambridge, UK
`
`Reply from the Authors: We thank Dr. Quattrone et al. for their
`comments about our article on manometry combined with cervical
`puncture in IIH.1 Our patients all had IIH, which is different from
`isolated intracranial hypertension without papilledema. There re-
`mains, however, a valid question as to the cause of the functional
`obstruction to cerebral venous outflow at the level of the TS. In
`our first paper, we considered mural thrombus, in some cases
`forming on arachnoidal granulations, the likely cause.10 However,
`in IIH, where cerebral venography typically shows smooth bilat-
`eral tapered narrowing rather than focal sessile lesions, we now
`think that the changes are all due to stretching of the walls of the
`TS, given the immediate relief of elevated venous sinus pressures
`by lowering intracranial pressure with cervical puncture.
`The case report of successful stenting of one TS in a patient
`with IIH5 confirmed our findings of a pressure drop across the TS
`with raised pressures at the level of the torcula. The stent in the
`TS abolished the venous hypertension, and after 3 weeks the
`opening pressure at lumbar puncture was normal. The stent
`opened the lumen of the TS, dropped the pressure in the superior
`sagittal sinus, and allowed passive absorption of CSF, thereby
`lowering the intracranial pressure. Lowering the intracranial
`pressure by C1–2 puncture has the same effect, which leads us to
`consider that the TS stenosis is caused by extrinsic pressure on
`the walls of the TS rather than by intraluminal processes, such as
`mural thrombus. This argument begs the question as to what
`flattens the walls of the TS. We believe there is some process in
`IIH involving the arachnoidal granulations that impairs CSF ab-
`sorption and initiates the rise in intracranial pressure.
`MRV is recognized to be sensitive to altered flow but less
`accurate in assessing the anatomy of the venous sinuses. We con-
`sider conventional venography to be superior to MRV in displaying
`anatomic detail, and at this stage the smooth bilateral narrowing of
`the TS in IIH is unlikely to be due to mural thrombus.
`
`964
`
`NEUROLOGY 59 September (2 of 2) 2002
`
`Dr. Lee has drawn attention to the uncertain place of MRV in
`IIH. In typical cases of IIH we found the MRV lacked adequate
`definition in the TS, and flow voids could easily be misinterpreted
`as sinus thrombosis. MRV and conventional cerebral venograms
`were performed in patients with IIH, and most patients showed
`apparent narrowing of the TS on MRV; however, T2- and T1-
`weighted MRI excluded thromboses and arachnoidal granulations.
`We did not perform pre- and postcervical puncture MRV but
`would be surprised if this technique would be helpful because
`conventional venography did not show striking changes despite
`lowering of pressures in the superior sagittal sinus and proximal
`TS after cervical puncture.
`Dr. Higgins and Professor Pickard question our conclusion that
`the venous outflow obstruction in IIH is due to partial collapse of the
`walls of the TS from raised intracranial pressure as a secondary
`phenomenon. By lowering intracranial pressure we found the pres-
`sure gradient in the TS largely disappeared. It is reasonable to as-
`sume that the cross-sectional area of the TS increased when the
`extrinsic compression was reduced. This would have the same effect
`as enlarging the internal dimensions by placement of a stent.
`Conventional venograms in most instances of IIH show smooth,
`tapered narrowing of the TS bilaterally. Although we originally felt
`this could be due to mural thrombus, it seems unlikely that such a
`symmetrical appearance could result from acute, organized, or re-
`canalized clot. If the process were some form of sclerosis of the TS,
`one would not expect lowering the intracranial pressure to have any
`significant effect on the venous hypertension.
`Our hypothesis requires a subclinical elevation of intracranial
`pressure, possibly due to some change in permeability of arachnoidal
`villi to CSF. This could be produced by an as yet unidentified hor-
`mone in overweight females or by drugs such as minocycline. Over a
`period of a few months, in susceptible individuals the raised intracra-
`nial pressure would start to flatten the walls of the TS and push up
`the venous pressure in the superior sagittal sinus and proximal TS,
`further impairing CSF absorption and sharply elevating intracranial
`pressure. Stenting one TS would allow venous pressure to fall, but
`would the intracranial pressure fall to normal, as happened in the
`case reported by Higgins et al?5 The early value of stenting the TS in
`IIH has been confirmed in a further four cases,11 and the procedure
`offers a new treatment option. The follow-up results are awaited;
`however, these cases suggest that cerebral venography and manom-
`etry should be done routinely in IIH.
`
`J.O. King, MD, FRACP, P.R. Mitchell, MBBS, FRACR,
`K.R. Thomson, MBBS, FRACR, B.M. Tress, MD, FRACR,
`Melbourne, Australia
`
`Copyright © 2002 by AAN Enterprises, Inc.
`
`References
`1. King JO, Mitchell PJ, Thomson KR, et al. Manometry combined with
`cervical puncture in idiopathic intracranial hypertension. Neurology
`2002;58:26–30.
`2. Quattrone A, Gambardella A, Carbone AM, et al. A hypofibrinolytic
`state in overweight patients with cerebral venous thrombosis and iso-
`lated intracranial hypertension. J Neurol 1999;246:1086–1089.
`3. Quattrone A, Bono F, Oliveri RL, et al. Cerebral venous thrombosis and
`isolated intracranial hypertension without papilledema in CDH. Neu-
`rology 2001;57:31–36.
`4. Leach JL, Jones BV, Tomsick TA, et al. Normal appearance of arach-
`noid granulations on contrast-enhanced CT and MR of the brain: differ-
`entiation from dural sinus disease. AJNR Am J Neuroradiol 1996;17:
`1523–1532.
`5. Higgins JN, Owler BK, Cousins C, et al. Venous sinus stenting for
`refractory benign intracranial hypertension. Lancet 2002;359:228–230.
`6. Lee AG, Brazis PW. Magnetic resonance venography in idiopathic
`pseudotumor cerebri. J Neuroophthalmology 2000;20:12–13.
`7. Corbett JJ, Digre K. Idiopathic intracranial hypertension: an answer to,
`“the chicken or the egg?” Neurology 2002;58:5–6.
`8. Osterholm J. Reaction of the cerebral venous system to acute intracra-
`nial hypertension. Neurosurg 1970;32:654–659.
`9. Piechnik SK, Czosnyka M, Richards HK, Whitfield PC, Pickard JD.
`Cerebral venous blood outflow: a theoretical model based on laboratory
`simulation. Neurosurgery 2001;49:1214–1223.
`10. King JO, Mitchell PR, Thomson KR, Tress BM. Cerebral venography
`and manometry in idiopathic intracranial hypertension. Neurology
`1995;45:2224–2228.
`11. Owler BK, Parker G, Dunn V, Halmagyi GM, McDowell D, Besser M.
`Pseudotumor cerebri: treatment with venous sinus stenting. Aus N Z
`J Surg 2002;72(suppl):A62.
`
`

`

`Economy class stroke syndrome
`Christian Foerch, Kirn R. Kessler, Helmuth Steinmetz, et al.
`2002;59;962-964
`Neurology 
`DOI 10.1212/WNL.59.6.962-b
`
`This information is current as of September 24, 2002
`
`Updated Information &
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