Mitochondrial Myopathy or Chronic Inflammatory
Demyelinating Polyneuropathy (CIDP)?
To the Editor.\p=m-\Bernsenand coworkrecently described a patient in whom they found a defect in mitochondrial complex 1 and carnitine deficiency in skeletal muscle. However, the clinical features of their patient suggest CIDP. These features include the course (progression over 3 months from normal to severely disabled); areflexia; slowing of motor nerve conduction to a degree that suggested
ers1
that the authors only used skeletal muscle specimens from patients with¬ out known neuromuscular disease for control specimens. Disease control specimens (including denervated muscle) would have been useful. David A. Krendel, MD The Emory Clinic Section of Neurology 1365 Clifton Rd NE Atlanta, GA 30322 1. Bernsen PL, Gabre\l=e"\lsFJ, Ruitenbeek W, Sengers RC, Stadhouders AM, Renier WO. Successful treatment of pure myopathy, associated with complex 1 deficiency, with riboflavin and
carnitine. Arch Neurol. DR. 2. Cornblath
1991;48:334-338.
Electrophysiology
in
Guillain-Barr\l=e'\syndrome. Ann Neurol. 1990;27
(suppl):S17-S20.
primary demyelination (presuming compound muscle action potential In Reply.\p=m-\Krendelsupposes that the amplitudes were not significantly de- patient whom we described1 might
creased\p=m-\informationnot provided in the article)2; and the elevated level of the cerebrospinal fluid protein. Proximal weakness is not uncommon in CIDP. Normal sensory conduction does not exclude the diagnosis, and, although normal histologic appearance of the sural nerve is unusual, it should not be incompatible with CIDP since the lesions are commonly multifocal and may preferentially involve motor fibers. The targetoid fibers and small angular fibers in the soleus muscle suggest denervation. Convincing evidence of myopathy is lacking. The electromyographic ab¬ normalities were predominantly neurogenic; the changes in the quadri¬ ceps that were described by the au¬ thors sound nonspecific; and the level of creatine kinase was normal. I do not think that the number of lipid droplets in their electron micrograph is abnormal, and electron microscopy should be more reliable than Sudan black staining for assessing this. The patient's apparent response to treatment may have another explana¬ tion. Chronic inflammatory demyeli¬ nating polyneuropathy is known to relapse and remit, and spontaneous recovery may have occurred, rather than a therapeutic response. The results of their biochemical studies are interesting, but I notice
have been
suffering from chronic inflammatory demyelinating polyneuropathy (CIDP). Initially, this disorder has ranked high in our differential diagnostic considerations and investigations (including sural nerve biopsy) were directed to confirm
exclude this condition. Howthe combination of the clinical signs and the results of additional investigations, such as symmetric proximal muscle weakness, normal sensation, normal sensory action potentials and latencies, normal histologic appearance of the sural nerve, and the absence of relapse to date, features that are individually rarely encountered in patients with CIDP, has made us reject the diagnosis of CIDP. We have reviewed our patient's muscle biopsy specimens, and we persist in our opinion that the quadriceps muscle specimen shows evidence of lipid storage on Sudan black stain and electron microscopic studies. The soleus biopsy specimen, on the contrary, showed evidence of denervation consistent with neuropathy that may be associated with mi¬ tochondria! disease. Mitochondrial respiratory chain enzyme activities have been determined in the quadri¬ ceps muscle biopsy specimen that showed no evidence of neurogenic involvement. So, we believe that the or
ever,
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/08/2015
enzyme activity levels were not in¬ fluenced by a primary neurogenic process. Furthermore, in our experi¬ ence, respiratory chain enzyme activ¬ ities in denervated muscle do not show a specific single enzyme defect. The quadriceps muscle biopsy speci¬ men showed a severe carnitine defi¬ ciency that is, to our knowledge, not found in CIDP. An increased creatine kinase level is infrequently found in cases of mitochondrial myopathy, so a normal level does not exclude this condition. In our opinion, the correct diagnosis remains a mitochondrial myopathy due to complex I defi¬ ciency, the more because our patient does not fulfill the mandatory diag¬ nostic criteria of CIDP that, among others, require exclusion of associ¬ ated or systemic disease.2 P. L. J. A. Bernsen, MD F. J. M. Gabre\l=e"\ls,MD, PhD W. Ruitenbeek, PhD H. J. ter Laak, PhD
Department of Child Neurology Institute of Neurology St Radboud University Hospital PO Box 9101 6500 HB Nijmegen the Netherlands
1. Bernsen PL, Gabre\l=e"\lsFJ, Ruitenbeek W, Sengers RC, Stadhouders AM, Renier WO. Suc-
cessful treatment of pure myopathy associated with complex 1 deficiency, with riboflavin and carnitine. Arch Neurol. 1991;48:334-338. 2. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41:617-618.
Visual Evoked Potentials and Intracranial Pressure To the Editor.\p=m-\Iread with interest the article by Connolly et al, entitled "Rapid Recovery From Cortical Visual Impairment Following Correction of Prolonged Shunt Malfunction and Congenital Hydrocephalus."1 The authors indicated that the three patients had long periods of elevated intracranial pressure secondary to shunt malfunction. They did not indicate how they knew that the pressure levels were elevated. Perhaps the patients
had prolonged periods of shunt malfunction leading to an increase in intracranial pressure because of the reluctance to invasively measure intracranial pressure. The authors did mention that visual evoked potentials were used for evaluations of the patients, but they did not indicate how these were obtained. Visual evoked potentials have been found helpful in noninvasively estimating intracranial pressure levels in patients with acute
hydrocephalus in shunts.2,3
Cardiovascular Investigation in Elderly Patients With Transient
Unresponsiveness
To the Editor.\p=m-\Haimovicand Beresford1 described five cases of transient unresponsiveness in elderly subjects. They claimed that those episodes "could not be explained by metabolic,
structural, convulsive, psychiatric disease," and that the speculation
about the causes included "diffuse cerebral ischemia, atypical generalized seizures, and a form of sleep disorfindder."1
Services Systems Room TBR58 22 S Greene St Baltimore, MD 21201-1595
ings are against psychiatric disorders, epileptic seizures, as well as pro-
Emergency
1. Connolly MB, Jan JE, Cochrane DD. Rapid recovery from cortical visual impairment following correction of prolonged shunt malfunction in
congenital hydrocephalus.
Arch Neurol. 1991;
48:956-957. 2. York DH, Pulliam MW, Rosenfeld JG, Watts C. Relationship between visual evoked potentials and intracranial pressure. J Neurosurg. 1981;55: 909-916. 3. York DH, Legan M, Benner D, Watts C. Further studies with a non-invasive method of intracranial pressure estimation. Neurosurgery.
1984;14:456-461.
In Reply.\p=m-\Allthree children described in our article1 were followed up by a pediatric neurosurgeon who obtained computed tomographic scans of the head before and after each shunt revision and also during follow-up. The lateral ventricles were dilated before and reduced in size after surgery. One child had chronic intracranial pres-
monitoring before revision, and the pressure level was elevated. Visual evoked potential studies were done in all children but, unfortunately, not consistently both before and after shunt revision. sure
M. B.
Connolly, MB, MRCPI, MRCP(UK) J. E. Jan, MD, FRCPC D. D. Cochrane, MD, FRCSC Children's Hospital 4480 Oak St Vancouver, British Columbia Canada V6H 3V4
1. Connolly MB, Jan JE, Cochrane DD. Rapid recovery from cortical visual impairment following correction of prolonged shunt malfunction in
congenital hydrocephalus. 48:956-957.
Arch Neurol. 1991;
Department of Neurology University of Genova
Via de Toni 5 16132 Genova,
or
Clark Watts, MD Department of Neurosurgery Maryland Institute for
Medical
vasive tests helpful in trying to identify the cause of the disorder of conscious¬ ness. In particular, Holter monitoring should be a routine investigation in elderly patients presenting with epi¬ sodes of transient unresponsiveness. Alberto Primavera, MD Massimo Del Sette, MD
Electroencephalographic
longed postictal encephalopathies.2 Furthermore, there is
based
no
evidence,
history or clinical findings, to support the sleep disorder hypothon
esis. Some of the patients described1 had risk factors for cardiovascular disease (patients 2, 4, and 5), one patient died of sudden death (patient 4), and one patient was admitted because of the presence of congestive heart
failure (patient 5). Thus, diffuse cerebral ischemia seems to be a likely cause of the episodes reported, at least in some cases. It is well known that cardiac dysrhythmias may be a cause, in elderly subjects, of transient unre¬ sponsiveness.3 In some of these cases, Holter monitoring can identify perti¬ nent arrhythmias despite the presence of a normal standard electrocardio¬ to gram.4 Acute hypotension, due of chronic hypovolemia, and failure cerebral autoregulation, especially if associated with carotid or vertebral severe stenosis, are thought to be other relevant causes of transient focal or diffuse cerebral dysfunction in eld¬ erly subjects.57 From among their pa¬ tients, Haimovic and Beresford listed only one in whom "an ECG [electro¬ was normal," but no pa¬ tient was registered continuously; pa¬ tient 1 was also the only one who had 24-hour electroencephalographic a monitoring performed, and patient 3 was the only one in whom a carotid an¬ giographie evaluation was per¬ formed.1 We think that, in some of these cases, a continuous monitoring of arterial blood pressure, electroencephalography, and electrocardiography, along with an evaluation of the state of the supra-aortic vessels (ie, Doppler examination) might be nonin-
cardiogram]
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/08/2015
Italy
1. Haimovic IC, Beresford RB. Transient unresponsiveness in the elderly: report of five cases.
Arch Neurol. 1992;49:35-37. 2. Biton V, Gates JR, Sussman L.
Prolonged postictal encephalopathy. Neurology. 1990;40:
963-966. 3. McCarthy ST, Wollner L. Cardiac dysrhythmias: treatable cause of transient cerebral dysfunction in the elderly. Lancet. 1977;1:202-203. 4. Jonas S, Klein I, Dimant J. Importance of Holter monitoring in patients with periodic cerebral symptoms. Ann Neurol. 1977;1:470-474. 5. Wollner L, McCarthy ST, Soper NDW,
Macy DJ. Failure of cerebral autoregulation cause
of brain
dysfunction
in the
as a
elderly. BMJ.
1979;1:1117-1118. 6. Mitchinson MJ. The hypotensive stroke. Lancet. 1980;1:244-246. 7. Sulkava R, Erkinjuntti T. Vascular dementia due to cardiac arrhythmias and systemic hypotension. Acta Neurol Scand. 1987;76:123-128.
In Reply.\p=m-\We appreciate the observations of Primavera and Del Sette about
the possibility that the reported1 episodes of unresponsiveness were caused by diffuse brain ischemia secondary to cardiac dysrhythmias. While we considered this possibility, evidence to
support
it
was
lacking. During
unre-
sponsiveness, the patients' electrocardiograms revealed no dysrhythmias, and at no time during their hospitalizations were dysrhythmias observed (including time of the Holter monitoring in one patient). This does not totally exclude the possibility that each episode was triggered by a transient dysrhythmia that did not persist into the often quite prolonged periods of unresponsiveness. But we believe that these observations weigh strongly against that possibility. Moreover, despite long periods of unresponsiveness (up to 5 hours), none of the patients exhibited
neurologic findings on regaining responsiveness, as we would have expected had they sustained brain ischemia severe enough to cause unresponsivness of this duration. new
Itzhak C. Haimovic, MD Richard Beresford, MD Manhasset, NY
1. Haimovic IC, Beresford RB. Transient unrein the elderly. Arch Neurol. 1992; 49:35-37.
sponsiveness
Demyelinating Polyneuropathy (CIDP)?
To the Editor.\p=m-\Bernsenand coworkrecently described a patient in whom they found a defect in mitochondrial complex 1 and carnitine deficiency in skeletal muscle. However, the clinical features of their patient suggest CIDP. These features include the course (progression over 3 months from normal to severely disabled); areflexia; slowing of motor nerve conduction to a degree that suggested
ers1
that the authors only used skeletal muscle specimens from patients with¬ out known neuromuscular disease for control specimens. Disease control specimens (including denervated muscle) would have been useful. David A. Krendel, MD The Emory Clinic Section of Neurology 1365 Clifton Rd NE Atlanta, GA 30322 1. Bernsen PL, Gabre\l=e"\lsFJ, Ruitenbeek W, Sengers RC, Stadhouders AM, Renier WO. Successful treatment of pure myopathy, associated with complex 1 deficiency, with riboflavin and
carnitine. Arch Neurol. DR. 2. Cornblath
1991;48:334-338.
Electrophysiology
in
Guillain-Barr\l=e'\syndrome. Ann Neurol. 1990;27
(suppl):S17-S20.
primary demyelination (presuming compound muscle action potential In Reply.\p=m-\Krendelsupposes that the amplitudes were not significantly de- patient whom we described1 might
creased\p=m-\informationnot provided in the article)2; and the elevated level of the cerebrospinal fluid protein. Proximal weakness is not uncommon in CIDP. Normal sensory conduction does not exclude the diagnosis, and, although normal histologic appearance of the sural nerve is unusual, it should not be incompatible with CIDP since the lesions are commonly multifocal and may preferentially involve motor fibers. The targetoid fibers and small angular fibers in the soleus muscle suggest denervation. Convincing evidence of myopathy is lacking. The electromyographic ab¬ normalities were predominantly neurogenic; the changes in the quadri¬ ceps that were described by the au¬ thors sound nonspecific; and the level of creatine kinase was normal. I do not think that the number of lipid droplets in their electron micrograph is abnormal, and electron microscopy should be more reliable than Sudan black staining for assessing this. The patient's apparent response to treatment may have another explana¬ tion. Chronic inflammatory demyeli¬ nating polyneuropathy is known to relapse and remit, and spontaneous recovery may have occurred, rather than a therapeutic response. The results of their biochemical studies are interesting, but I notice
have been
suffering from chronic inflammatory demyelinating polyneuropathy (CIDP). Initially, this disorder has ranked high in our differential diagnostic considerations and investigations (including sural nerve biopsy) were directed to confirm
exclude this condition. Howthe combination of the clinical signs and the results of additional investigations, such as symmetric proximal muscle weakness, normal sensation, normal sensory action potentials and latencies, normal histologic appearance of the sural nerve, and the absence of relapse to date, features that are individually rarely encountered in patients with CIDP, has made us reject the diagnosis of CIDP. We have reviewed our patient's muscle biopsy specimens, and we persist in our opinion that the quadriceps muscle specimen shows evidence of lipid storage on Sudan black stain and electron microscopic studies. The soleus biopsy specimen, on the contrary, showed evidence of denervation consistent with neuropathy that may be associated with mi¬ tochondria! disease. Mitochondrial respiratory chain enzyme activities have been determined in the quadri¬ ceps muscle biopsy specimen that showed no evidence of neurogenic involvement. So, we believe that the or
ever,
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/08/2015
enzyme activity levels were not in¬ fluenced by a primary neurogenic process. Furthermore, in our experi¬ ence, respiratory chain enzyme activ¬ ities in denervated muscle do not show a specific single enzyme defect. The quadriceps muscle biopsy speci¬ men showed a severe carnitine defi¬ ciency that is, to our knowledge, not found in CIDP. An increased creatine kinase level is infrequently found in cases of mitochondrial myopathy, so a normal level does not exclude this condition. In our opinion, the correct diagnosis remains a mitochondrial myopathy due to complex I defi¬ ciency, the more because our patient does not fulfill the mandatory diag¬ nostic criteria of CIDP that, among others, require exclusion of associ¬ ated or systemic disease.2 P. L. J. A. Bernsen, MD F. J. M. Gabre\l=e"\ls,MD, PhD W. Ruitenbeek, PhD H. J. ter Laak, PhD
Department of Child Neurology Institute of Neurology St Radboud University Hospital PO Box 9101 6500 HB Nijmegen the Netherlands
1. Bernsen PL, Gabre\l=e"\lsFJ, Ruitenbeek W, Sengers RC, Stadhouders AM, Renier WO. Suc-
cessful treatment of pure myopathy associated with complex 1 deficiency, with riboflavin and carnitine. Arch Neurol. 1991;48:334-338. 2. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41:617-618.
Visual Evoked Potentials and Intracranial Pressure To the Editor.\p=m-\Iread with interest the article by Connolly et al, entitled "Rapid Recovery From Cortical Visual Impairment Following Correction of Prolonged Shunt Malfunction and Congenital Hydrocephalus."1 The authors indicated that the three patients had long periods of elevated intracranial pressure secondary to shunt malfunction. They did not indicate how they knew that the pressure levels were elevated. Perhaps the patients
had prolonged periods of shunt malfunction leading to an increase in intracranial pressure because of the reluctance to invasively measure intracranial pressure. The authors did mention that visual evoked potentials were used for evaluations of the patients, but they did not indicate how these were obtained. Visual evoked potentials have been found helpful in noninvasively estimating intracranial pressure levels in patients with acute
hydrocephalus in shunts.2,3
Cardiovascular Investigation in Elderly Patients With Transient
Unresponsiveness
To the Editor.\p=m-\Haimovicand Beresford1 described five cases of transient unresponsiveness in elderly subjects. They claimed that those episodes "could not be explained by metabolic,
structural, convulsive, psychiatric disease," and that the speculation
about the causes included "diffuse cerebral ischemia, atypical generalized seizures, and a form of sleep disorfindder."1
Services Systems Room TBR58 22 S Greene St Baltimore, MD 21201-1595
ings are against psychiatric disorders, epileptic seizures, as well as pro-
Emergency
1. Connolly MB, Jan JE, Cochrane DD. Rapid recovery from cortical visual impairment following correction of prolonged shunt malfunction in
congenital hydrocephalus.
Arch Neurol. 1991;
48:956-957. 2. York DH, Pulliam MW, Rosenfeld JG, Watts C. Relationship between visual evoked potentials and intracranial pressure. J Neurosurg. 1981;55: 909-916. 3. York DH, Legan M, Benner D, Watts C. Further studies with a non-invasive method of intracranial pressure estimation. Neurosurgery.
1984;14:456-461.
In Reply.\p=m-\Allthree children described in our article1 were followed up by a pediatric neurosurgeon who obtained computed tomographic scans of the head before and after each shunt revision and also during follow-up. The lateral ventricles were dilated before and reduced in size after surgery. One child had chronic intracranial pres-
monitoring before revision, and the pressure level was elevated. Visual evoked potential studies were done in all children but, unfortunately, not consistently both before and after shunt revision. sure
M. B.
Connolly, MB, MRCPI, MRCP(UK) J. E. Jan, MD, FRCPC D. D. Cochrane, MD, FRCSC Children's Hospital 4480 Oak St Vancouver, British Columbia Canada V6H 3V4
1. Connolly MB, Jan JE, Cochrane DD. Rapid recovery from cortical visual impairment following correction of prolonged shunt malfunction in
congenital hydrocephalus. 48:956-957.
Arch Neurol. 1991;
Department of Neurology University of Genova
Via de Toni 5 16132 Genova,
or
Clark Watts, MD Department of Neurosurgery Maryland Institute for
Medical
vasive tests helpful in trying to identify the cause of the disorder of conscious¬ ness. In particular, Holter monitoring should be a routine investigation in elderly patients presenting with epi¬ sodes of transient unresponsiveness. Alberto Primavera, MD Massimo Del Sette, MD
Electroencephalographic
longed postictal encephalopathies.2 Furthermore, there is
based
no
evidence,
history or clinical findings, to support the sleep disorder hypothon
esis. Some of the patients described1 had risk factors for cardiovascular disease (patients 2, 4, and 5), one patient died of sudden death (patient 4), and one patient was admitted because of the presence of congestive heart
failure (patient 5). Thus, diffuse cerebral ischemia seems to be a likely cause of the episodes reported, at least in some cases. It is well known that cardiac dysrhythmias may be a cause, in elderly subjects, of transient unre¬ sponsiveness.3 In some of these cases, Holter monitoring can identify perti¬ nent arrhythmias despite the presence of a normal standard electrocardio¬ to gram.4 Acute hypotension, due of chronic hypovolemia, and failure cerebral autoregulation, especially if associated with carotid or vertebral severe stenosis, are thought to be other relevant causes of transient focal or diffuse cerebral dysfunction in eld¬ erly subjects.57 From among their pa¬ tients, Haimovic and Beresford listed only one in whom "an ECG [electro¬ was normal," but no pa¬ tient was registered continuously; pa¬ tient 1 was also the only one who had 24-hour electroencephalographic a monitoring performed, and patient 3 was the only one in whom a carotid an¬ giographie evaluation was per¬ formed.1 We think that, in some of these cases, a continuous monitoring of arterial blood pressure, electroencephalography, and electrocardiography, along with an evaluation of the state of the supra-aortic vessels (ie, Doppler examination) might be nonin-
cardiogram]
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/08/2015
Italy
1. Haimovic IC, Beresford RB. Transient unresponsiveness in the elderly: report of five cases.
Arch Neurol. 1992;49:35-37. 2. Biton V, Gates JR, Sussman L.
Prolonged postictal encephalopathy. Neurology. 1990;40:
963-966. 3. McCarthy ST, Wollner L. Cardiac dysrhythmias: treatable cause of transient cerebral dysfunction in the elderly. Lancet. 1977;1:202-203. 4. Jonas S, Klein I, Dimant J. Importance of Holter monitoring in patients with periodic cerebral symptoms. Ann Neurol. 1977;1:470-474. 5. Wollner L, McCarthy ST, Soper NDW,
Macy DJ. Failure of cerebral autoregulation cause
of brain
dysfunction
in the
as a
elderly. BMJ.
1979;1:1117-1118. 6. Mitchinson MJ. The hypotensive stroke. Lancet. 1980;1:244-246. 7. Sulkava R, Erkinjuntti T. Vascular dementia due to cardiac arrhythmias and systemic hypotension. Acta Neurol Scand. 1987;76:123-128.
In Reply.\p=m-\We appreciate the observations of Primavera and Del Sette about
the possibility that the reported1 episodes of unresponsiveness were caused by diffuse brain ischemia secondary to cardiac dysrhythmias. While we considered this possibility, evidence to
support
it
was
lacking. During
unre-
sponsiveness, the patients' electrocardiograms revealed no dysrhythmias, and at no time during their hospitalizations were dysrhythmias observed (including time of the Holter monitoring in one patient). This does not totally exclude the possibility that each episode was triggered by a transient dysrhythmia that did not persist into the often quite prolonged periods of unresponsiveness. But we believe that these observations weigh strongly against that possibility. Moreover, despite long periods of unresponsiveness (up to 5 hours), none of the patients exhibited
neurologic findings on regaining responsiveness, as we would have expected had they sustained brain ischemia severe enough to cause unresponsivness of this duration. new
Itzhak C. Haimovic, MD Richard Beresford, MD Manhasset, NY
1. Haimovic IC, Beresford RB. Transient unrein the elderly. Arch Neurol. 1992; 49:35-37.
sponsiveness
