In their very interesting paper on the assessment of personality in
patients with epileptic (ES) and psychogenic non-epileptic seizures (PNES)
Reuber and colleagues conclude that maladaptive personality in patients
with PNES is common, reminiscent of Borderline Personality Disorder (BPD)
in a large subgroup and can be distinguished from non-clinical controls
and patients with epilepsy alone.[1]
In their very interesting paper on the assessment of personality in
patients with epileptic (ES) and psychogenic non-epileptic seizures (PNES)
Reuber and colleagues conclude that maladaptive personality in patients
with PNES is common, reminiscent of Borderline Personality Disorder (BPD)
in a large subgroup and can be distinguished from non-clinical controls
and patients with epilepsy alone.[1]
However, while this observation clearly
supports the need for a thorough psychiatric assessment and treatment of
patients with chronic and difficult to treat epilepsies the suggestion
that personality pathology distinguishes patients with PNES from patients
with epilepsy alone is questionable. Patients with ES alone scored higher
on many lower order personality traits in that very study. Furthermore,
119 of 329 identified patients with PNES were excluded because of evidence
of concurrent or previous true epilepsy. This subgroup of somewhat 36% of
patients with PNES and ES at the same time could have served as a very
interesting "intermediate" control group. The dimensional rather than
categorical approach to classify personality traits should be extended to
the etiological and pathogenetic thinking of any personality pathology.
Non-epileptic EEG abnormalities are very common in patients with BPD [2] and
in addition there is an increasing body of evidence for structural and
neurochemical brain abnormalities in these patients.3 Thus the term
psychogenic in PNES might well be misleading and chronic subclinical
epileptic or epilepsy associated brain dysfunction might well play a role
in the pathogenesis of PNES and other dissociative symptoms in patients
with epilepsy and/or PNES but also in patients with BPD. Most importantly,
the suggestion that the presence of a personality disorder might help to
distinguish PNES from ES clinically is dangerous because personality
disorders are very difficult to establish, common in the general
population and unspecific. Therefore their presence is not a good
indicator for the attribution of seizure to PNES or ES.
References
1. Reuber M, Pukrop R, Bauer J, Derfuss R, Elger CE.
Multidimensional assessment of personality in patients with psychogenic
non-epileptic seizures. J.Neurol.Neurosurg.Psychiatry 2004;75:743-8.
2. De la Fuente JM. Electroencephalographic abnormalities in
borderline personality disorder. Psychiatry Research 1998;77:131-8.
3. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K,
Lemieux L, Lieb K, Bohus M, Hennig J, Ebert D. Frontolimbic brain
abnormalities in patients with borderline personality disorder: a
volumetric magnetic resonance imaging study. Biological Psychiatry
2003;54:163-71.
Benzodiazepines are now the most prescribed group of
psychoactive drugs, and their safety for therapeutic use
has been established, but there also is the potential for
abuse and addiction.[1]
Endozepine stupor (ES) is
characterized by repeated, spontaneous stuporous attacks
lasting several hours or days, and responsiveness to
flumazenil without administration of benzodiazepine. ES is
caused by...
Benzodiazepines are now the most prescribed group of
psychoactive drugs, and their safety for therapeutic use
has been established, but there also is the potential for
abuse and addiction.[1]
Endozepine stupor (ES) is
characterized by repeated, spontaneous stuporous attacks
lasting several hours or days, and responsiveness to
flumazenil without administration of benzodiazepine. ES is
caused by "Endozepine-4", an endogenous benzodiazepine
receptor ligand, but not by benzodiazepines.[2] ES is
difficult to distinguish benzodiazepine intoxication based
on the clinical symptoms alone.
We read with great interest the paper by Granot et al,[3] because we experienced a similar patient of recurrent
stuporous episodes which were similar to ES, but caused by
suspected covert administration of benzodiazepines.
Case report
A 45 year-old man suddenly experienced spontaneous comatose
episodes once or twice a week. These episodes started with
the sudden complaint of dizziness. He talked and walked
like a drunk, then became disoriented. Drowsiness finally
progressed to a stuporous state and deep sleep. That state
lasted 8 to 12 hours, after which he woke spontaneously and
recovered. The episodes occurred at various times during
the day. He was taken to a hospital near his home several
times. Each time, he recovered without specific treatment.
The factors and cause that triggered the episodes were not
evident. He desired a detailed examination and presented at
our hospitals. He had been divorced and remarried and had a
daughter who was hospitalized due to pulmonary
hypertension.
In the interictal phase, the physical and neurological
examinations were normal. Blood and urinary tests; glucose,
electrolytes, hormones, anmonia, pyruvate, lactate, amino
acid analysis, and arterial blood gas, were all normal.
Cerebrospinal fluid also was normal. No specific
abnormalities were detected by brain magnetic resonance
imaging. Electroencephalography (EEG) showed rhythmic 9-10
Hz background activity with no abnormalities. In the ictal
phase, his blood pressure was stable and there was no
arrhythmia. Blood examinations were all normal. A high
performance liquid chromatography assay detected no
clonazepam, diazepam, and nitrazepam in his blood. EEG
showed diffuse, generalized 14 Hz fast waves and occasional
6 Hz slow wave. Intravenous administration of flumazenil
(0.5mg) woke him rapidly, and EEG rapidly became
normalized. Based on our observations and findings, we
tentatively considered him as having ES. However, after he
again was divorced, he told us that he no longer suffered
these episodes.
To obtain further information about his episodes, we
performed an immunoenzymatic assay (Triage-8, Biosite, CA,
USA) which showed a trace of benzodiazepine in his stored
urine samples from the ictal phase. We performed gas
chromatography-mass spectroscopy to identify the specific
benzodiazepine present in his serum and urine collected
during the episode. Brotizolam was detected in his serum
(24.8 ng/ml) and urine (650 ng/ml). Its concentration in
his serum corresponded to a concentration one to two hours
after oral ingestion of more than 1.5-2 mg brotizolam;
enough to explain his consciousness disturbance.
Comment
Recurrent consciousness disturbance in this patient's case
was caused by brotizolam intoxication, and the gas
chromatography-mass spectroscopy was required to exclude
the possibility of ES. When diagnosing and treating drug
intoxication, it is essential to clarify what kind and what
quantity of the drugs the patient has taken. It is also
essential to ascertain the reasons for taking drugs. When
as in our patient's case, the reasons for drug intoxication
are not clear, ES was difficult to distinguish
benzodiazepine intoxication based on the clinical symptoms
alone. The clinical setting of a pleasant gentleman, always
accompanied by his worried wife, gave no reason to suspect
drug abuse. As Granot et al. have suggested, we should look
at "the patient's ever present partner" instead of the
literature,[3] and we also agreed with Simini's advice that
"the gullibility of the experts might surpass that of the
lay".[4]
Although a remarkable property of the benzodiazepines is
their relative safety after an overdose, the outcome of
abuse and covert administration of benzodiazepine may be
dangerous or fatal when these kinds of drugs are ingested
together with ethanol or other sedative agents, especially
in the elderly and in patients with lung diseases1. It is
therefore important that the possibility of benzodiazepine
intoxication be carefully ruled out in the cases of
consciousness disturbance. The description of the disease
entity of ES reveals a hidden aspect in diagnosis of these
conditions. Although differential diagnosis of stupor is a
common problem in emergency or neurology department,[3]
immunoenzymatic assays to detect benzodiazepines are
reported to give false-negatives as well as false-
positive1. Furthermore, Lugaresi et al. pointed out that
much effort was required to detect some benzodiazepines
such as lorazepam.[5] Thus, a proposal of such novel
disease entity may highlight the difficulty in diagnosis of
benzodiazepine intoxication and detecting blood and urine
benzodiazepine. Further studies are still needed, and
continued research should clarify once and for all whether
all cases of recurrent stupor involve the covert
administration of a benzodiazepine, as well as the detailed
pathogenesis of ES, as Riva et al. [6] have suggested.
Acknowledgment
We are grateful to Professor Elio Lugaresi of University
of Bologna, and Professor Jeffery Rothstein of Johns
Hopkins Hospital for their suggestions and encouragement of
our clinical study of this patient. We also are grateful to
the members of Mitsubishi Biochemical Laboratory (MBC) for
their collaboration.
References
1 Farrell SE, Benzodiazepine, In: Ford MD, Delaney KA, Ling
LT, Erickson T eds. Clinical toxicology. Pennsylvania: W.B.
Saunders, 2001:575-81.
We greatly appreciate the considerable and thoughtful
comments offered by Boris Kotchoubey and his interest in
our report of three cases in a persistent vegetative state
(PVS) after severe head injury, who recovered from a
prolonged disturbance of consciousness after the
administration of levodopa.[1]
As author points it out, PVS patient present a wide range
of neurological symptoms and syndro...
We greatly appreciate the considerable and thoughtful
comments offered by Boris Kotchoubey and his interest in
our report of three cases in a persistent vegetative state
(PVS) after severe head injury, who recovered from a
prolonged disturbance of consciousness after the
administration of levodopa.[1]
As author points it out, PVS patient present a wide range
of neurological symptoms and syndromes in addition to their
main symptoms. According to the description by Jennet and
Plum, PVS is the condition of patients with severe brain
damage in whom coma has progressed to a state of
wakefulness without detectable awareness. In this state,
there is the absence of any adaptive response to the
external environment, the absence of any evidence of a
functioning mind which is either receiving and projecting
information.[2,3] The widely accepted criteria of PVS are
those in the 1994 report from the US Task Force.[4,5] In
this report, PVS was defined in detail and distinguished
from the other related conditions such as coma, brain
death, locked-in syndrome, akinetic mutism, and dementia.
The causes of PVS, however, include various pathogenesis
such as trauma, hypoxic ischemic damage, cerebrovascular
injury, infection, tumor, toxins or poisoning.[4] After
all, the concept of PVS seems to be the entity of
"syndrome" that contains some typical symptoms and variable
pathogenesis. The advantage of the term "vegetative state" is that it simply describes observed behavior, without
implying specific structural pathology.[5] On considering
these points, the cases we presented may be a subgroup
among a large group of PVS patients.
Some individuals whose dopaminergic systems may have been
selectively damaged could be latent among majority of the
patients in a PVS after severe head injury and only such
individuals may respond to levodopa treatment.[1,6]
Similarly, another individuals whose another neural systems
may be damaged must be latent among a PVS and such
individuals may respond to another treatment such as
another specific stimulative agent (including
neurotransmitter), deep brain stimulation, or intensive
rehabilitation. We should not regard it as unitary entity.
Probably, there is no single method to treat all the PVS
patients. PVS should be divided to many subgroups according
to its pathogenesis. Thus, when we decide the treatment for
PVS patients, it should be in line with the anatomical and
physiological mechanism of each case. To investigate the
pathogenesis like that, newer diagnostic concept of
disturbance of consciousness and radiographic tool for
prognostic factor of vegetative state would probably be
useful and helpful in future.[7,8]
In a point of statement above, the comments that Kotchoubey mentioned are very important. These points were touched
upon in our report [1] and our reply to corresponding
letter,[6] and we would like to agree with the view of him
that it may be a wrong strategy to search for a treatment
for the PVS in general. We are very glad that author has
brought up these questions and points of view now. To give
a definitive answer to this question, we will have to
continue to our study and obtain more data and clinical
experience. Finally, once again, we should not generalize
the PVS as a unitary entity.
References
1. Matsuda W, Matsumura A, Komatsu Y, Yanaka K, and Nose T.
Awakenings from persistent vegetative state: report of
three cases with parkinsonism and brain stem lesions on
MRI. J Neurol Neurosurg Psychiatry 2003; 74:1571-3
2. Jennet B, Plum F. Persistent vegetative state after
brain damage: a syndrome in search of a name. Lancet 1972;
1: 734-7
3. Zeman A. Persistent vegetative state. Lancet 1997; 350:
795-9
4. The Multi-Society Task Force On PVS. Medical aspects of
the persistent vegetative state. N Engl J Med 1994; 330:
1499-1508
5. Jennet B. The vegetative state. J Neurol Neurosurg
Psychiatry 2002; 73: 355-7
6. Matsuda W, Matsumura A, Komatsu Y, and Yanaka K. Author
's reply to ÒParkinsonism and persistent vegetative state
after head injuryÓ by Kurt A. Jellinger. J Neurol
Neurosurg Psychiatry (Corresponding letter, in press) 2004
7. Giacino JT, Ashwal S, Childs N, Cranford R, Jennet B,
Katz DI, Kelly JP, Rosenberg JH, Whyte J, Zafonte RD,
Zasler ND. The minimally conscious state: Definition and
diagnostic criteria. Neurology 2002; 58: 349-353
8. Uzan M, Albayram S, Dashti SGR, Aydin S, Hanci M, Kuday
C. Thalamic proton magnetic resonance spectroscopy in
vegetative state induced by traumatic brain injury. J
Neurol Nerurosurg Psychiatry 2003; 74: 33-38
The Short Report by Ago and colleagues,[1] describing deterioration
of pre-existing left hemiparesis by a subsequent ipsilateral hemispheric
insult, contains a laterality-indexed aspect related to motor control in
humans, not addressed by the authors.
Cases similar to their patient are on record.[2] The explanation of
the laterality indexed bilateral activation of motor cortices (or, as in...
The Short Report by Ago and colleagues,[1] describing deterioration
of pre-existing left hemiparesis by a subsequent ipsilateral hemispheric
insult, contains a laterality-indexed aspect related to motor control in
humans, not addressed by the authors.
Cases similar to their patient are on record.[2] The explanation of
the laterality indexed bilateral activation of motor cortices (or, as in
the case reported by Ago et al, activation of the cortex ipsilateral to
the nondominant hand, Figure 1) is based on the fact that all movements are
initiated from the major hemisphere, with those involving effectors
ipsilateral to the major hemisphere requiring transfer of the command
signal to the minor hemisphere via the callosum (for implementation of the
signal by the minor hemisphere). This is the newly discovered anatomy of
handedness.[3,4] This also is the explanation the findings in all of
the articles to which the authors referred, erroneously ascribed to
plasticity/reorganisation of the unaffected hemisphere. Among those
articles the time-pegged EEG/EMG study by Green et al. [5] is the most
instructive, documenting an average 100 ms delay when the right handed
participants moved their left fingers as compared to moving the right.
This delay is the interhemispheric transfer time alluded to above.
Incidentally, cases 2 and 4 in Green et al.’s study were ostensible right
and neural left handers wherein the timing of events were the reverse.[3-
5] (I am assuming here that Ago’s case was a right hander).
Similarly, the nondominant delay just mentioned is inconsistent with
Ago et al's suggested ipsilateral/direct corticospinal pathway; i.e. from
the major hemisphere to the left side (the existence of which in humans
lacks any proof).
Thus, the worsening of the condition of the left side of their
patient after a new insult to the major hemisphere was the result of
diaschitic de-afferentation of the minor hemisphere from the excitatory
influences originating in the major hemisphere, described elsewhere.[3,4]
References
1. Ago T, Kitazono H, Ooboshi H, et al. Deterioration of pre-existing
hemiparesis brought about by subsequent ipsilateral lacunar infarction. J
Neurol Neurosurg Psychiatry 2003; 74: 1152-1153.
2. Nathan PW, Smith MC. Effects of two unilateral cordotomies on the
motility of the lower limbs. Brain 1973; 96:471-494. (Case 103; see table
1 and pages 471, 487-488)
3. Derakhshan I. Callosum and movement control; case reports. Neurol
Res 2003; 25: 538-542.
4. Derakhshan I, Hund-Georgiadis, von Cramon, DY. Impaired
hemodynamics and neural activation? A fMRI study of major cerebral artery
stenosis. Neurology 2003; Dec. 4, 2003, in press & at
www.neurology.org/cgi/eletters/61/9/1276
5. Green JB, Bialy Y, Sora E, Ricamato A, et al. High-resolution EEG
in poststroke hemiparesis can identify ipsilateral generators during motor
tasks. Stroke 1999; 30: 2659-2665.
Matsuda et al.[1] reported three cases of patients with traumatic
persistent vegetative state (PVS), in which an active treatment with
levodopa, starting after 3, 7, and 12 months, respectively, resulted in
fast recovery of consciousness.
All three patients had parkinsonian
symptoms and MRI evidence of the damage to the substantia nigra or ventral
tegmental area. This is an astonishing r...
Matsuda et al.[1] reported three cases of patients with traumatic
persistent vegetative state (PVS), in which an active treatment with
levodopa, starting after 3, 7, and 12 months, respectively, resulted in
fast recovery of consciousness.
All three patients had parkinsonian
symptoms and MRI evidence of the damage to the substantia nigra or ventral
tegmental area. This is an astonishing report given the well-known
inefficiency of most treatment techniques in PVS.[2,3]
One can object, however, that both Parkinsonism and the midbrain lesions
are not very typical for PVS in general, and that, therefore, the authors'
success was due to the selection of a particular, very specific subgroup
of PVS patients. This is correct. But let's think this idea one step
further. It is based on the implicit assumption that there is such thing
as "the" PVS, and that the presence of additional symptoms (like
Parkinsonism in Matsuda et al.[1]) always indicates a deviation from
some "classical" PVS pattern.
This assumption is not self-evident, though. In fact, PVS patients present
a wide range of neurological symptoms and syndromes, such as pareses,
disorders of vision, or various disturbances of the sleep pattern, in
addition to their main symptomatics, i.e. the lack of behavioral
responses. Do we need to remove all patients with such additional symptoms
from our experimental groups in order to obtain the "pure" PVS? And, if we
do this selection scrupulously, how many will remain in the rest?
An alternative may be to regard PVS, like any other neurological
disease, as a multi-facet complex consisting of a well-defined "core" and
a set of subgroups. Such subgroups may, or may not, possess a pathogenetic
specificity like the midbrain lesions in the patients of Matsuda et al.[1] If this view is correct, it may be a wrong strategy to search for
a treatment for the PVS in general. Hence, it should not be surprising
that this search has been so unsuccessful to date. Another strategy is
looking for particular subsets of symptoms characterizing a different
subgroups of PVS patients. The treatment is, then, aimed at a specific key
mechanisms of pathogenesis in these patients. A unitary view of PVS should
not be an obstacle to look for those curative methods which may help in
particular cases. At the very least, for a patient who regained
consciousness, it does not matter whether he should thank to a generalized
or a specific treatment.
References
(1) W Matsuda, A Matsumura, Y Komatsu, K Yanaka, and T Nose. Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 2003; 74: 1571-1573
(2) Giacino JT. The effects of cognitive rehabilitation on outcomes for
persons with traumatic brain injury: A systematic review. Journal Head
Trauma Rehabilitation 2000; 15: ix-x.
(3) Jennett B. The Vegetative State. Cambridge, UK: University Press, 2002.
Matsuda W, Matsumura A, Komatsu Y, Yanaka K, Nose T. Awakenings from
persistent vegetative state: Report of three cases with Parkinsonism and
brain stem lesions on MRI. Journal of Neurology, Neurosurgery and
Psychiatry 2003; 74: 1571-1573.
Regarding Ginsberg's article: Difficult and recurrent.[1]
The rationale underlying the author's use of a frequent dosing
regimen for antibiotics in acute bacterial meningitis is a sound one,
namely to compensate for the eventuality of missed doses,[1] the latter
being one of the realities in a service tightly stretched for manpower.
The unequivocal recommendation for a 4-hour dosing regime f...
Regarding Ginsberg's article: Difficult and recurrent.[1]
The rationale underlying the author's use of a frequent dosing
regimen for antibiotics in acute bacterial meningitis is a sound one,
namely to compensate for the eventuality of missed doses,[1] the latter
being one of the realities in a service tightly stretched for manpower.
The unequivocal recommendation for a 4-hour dosing regime for cefotaxime
in pneumococcal meningitis(ie 2g every 4 hours) resonates with this
concept.[2] What is hard to understand is why the handbook which is most
widely read by "frontline" junior doctors still adheres to the 8-hourly
regime, namely, cefotaxime 2-4 g 8-hourly in pneumococcal meningitis,[3]
given the fact that the fatality rate for pneumococcal meningitis has been
cited as being in the region of 20-
40%,[4] and also in the light of the evidence that cefotaxime doses in
the region of 18-24 g/d are well tolerated and have a high success rate
in adult meningitis due to streptococcus pneumoniae with decreased
susceptibilities to broad spectrum cephalosporins.[5]
References
(1) Ginsberg L. Difficult and recurrent meningitis
Journal of Neurology Neurosurgery and Psychiatry 2004:75
Supplement 1:i16-i21
(2) Warrell DA., Farrar JJ., Crook DWM. Bacterial Meningitis
In Oxford Textbook of Medicine Fourth Edition 2003:Chapter 24.14 Editors
Warrell DA., Cox TM., Firth JD., Benz EJ. Oxford University Press
(3) Longmore M., Wilkinson I., Torok E. Meningitis
In Oxford Handbook of Clinical Medicine Fifth Edition page 360 Editors
Longmore M., Wilkinson I., Torok E
Oxford University Press
(4) Pfister H-S., Feiden W., Einhaupl K-M. Spectrum of complications
during bacterial meningitis in adults
Archive of Neurology 1993:50:575-81
(5) Viladrich PF., Cabellos C., Pallares R., et al. High doses of
cefotaxime in treatment of adult meningitis due to streptococcus
pneumoniae with decreased susceptibilities to broad spectrum
cephalosporins Antimicrobial Agents and
Chemotherapy 1996:40:218-20
I read with interest that Wilson et al.[1] have confirmed an
association between depressive symptoms and subsequent cognitive decline
in a large defined community followed prospectively for an average of 5.3
years. The various possible explanations were discussed by Stewart.[2]
I wish to draw attention to one possible biological model of the risk
factor or prodromal interpretation of th...
I read with interest that Wilson et al.[1] have confirmed an
association between depressive symptoms and subsequent cognitive decline
in a large defined community followed prospectively for an average of 5.3
years. The various possible explanations were discussed by Stewart.[2]
I wish to draw attention to one possible biological model of the risk
factor or prodromal interpretation of this association, i.e. impairment of
methylation in the brain leading to depression and ultimately cognitive
decline on a background of ageing.[3]
In the brain methyl folate is the major source of methyl groups
which, in reactions involving S-adenosyl methionine and homocysteine, are
donated in innumerable methylation processes involving neurotransmitters,
monoamines, membrane phospholipids, proteins, RNA and DNA, the latter
influencing gene integrity and expression.[3,4]
I have elsewhere reviewed the evidence in neurological, psychiatric,
geriatric and psychogeriatric patients that the commonest neuropsychiatric
manifestation of folate deficiency is depression.[3] Impaired folate
metabolism may result in a pattern of cognitive dysfunction that resembles
ageing.[3] In elderly people folate deficiency contributes to ageing
brain processes, increases the risk of Alzheimer’s disease and vascular
dementia, and, if critically severe, can lead to a reversible dementia.[3] Recently identified common single nucleotide polymorphisms of
several genes coding for folate dependent enzymes increase these risks,
especially if associated with impaired nutritional folate status.[4]
A biological sub-group of patients with depression with raised plasma
homocysteine associated with impaired methylation and monoamine metabolism
has been identified.[5] Raised plasma homocysteine is also a risk factor
for Alzheimer’s and non-Alzheimer’s dementia [6] and for vascular disease.[4]
Stewart [2] rightly emphasises the need for more careful evaluation
of individual depressive symptoms or their clustering in relation to
subsequent cognitive decline. In disorders of methylation the key
symptoms are impaired mood and motivation.[3] Future studies of these
associations and relationships should include measures of methylation such
as red cell folate, plasma homocysteine and screening for polymorphisms of
genes for folate dependent enzymes. Brain methylation status and mood are
very poorly related to blood counts or serum folate.[3] Controlled
prospective studies are also needed of the potential to prevent cognitive
decline with prophylactic methyl folate.
References
1. Wilson RS, Mendes de Leon CF, Bennett DA et al. Depressive
symptoms and cognitive decline in a community population of older persons.
J Neurol Neurosurg Psychiatry 2004; 75: 126-9.
2. Stewart R. Depressive symptoms and cognitive decline –
disentangling the effect of affect. J Neurol Neurosurg Psychiatry 2004;
75: 5.
4. Lucock M. Is folic acid the ultimate functional food component for
disease prevention? BMJ 2004; 328: 211-4.
5. Bottiglieri T, Laundy M, Crellin R et al. Homocystine, folate,
methylation, and monoamine metabolism in depression. J Neurol Neurosurg
Psychiatry 2000; 69: 228-32.
6. Seshaderi S, Beiser A, Selhub J et al. Plasma homocysteine as a
risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346:
476-83.
Although our study was designed to investigate rTMS add-on effects in
an aggressive stimulation paradigm [2] we did not find a significant
difference between the active group (n= 25) in comparison to sham (n=13)
in a two week trial. Although we used aggressive parameters in an add-on
setting neurocognitive measure even slightly improved in the acti...
Although our study was designed to investigate rTMS add-on effects in
an aggressive stimulation paradigm [2] we did not find a significant
difference between the active group (n= 25) in comparison to sham (n=13)
in a two week trial. Although we used aggressive parameters in an add-on
setting neurocognitive measure even slightly improved in the active group.[3] Despite the lack of significant antidepressant effects, we had the
clinical impression of actively treated doing somewhat better in
comparison to sham stimulated patients. Although the number of recruited
patients is rather small, we, beside Klein et al,[4] recruited the
second largest sample of patients suffering from depression ever recruited
to an rTMS trial. We included confidence intervals to the manuscript to
inform the reader of the size of effect that was missed.
In the discussion
section we pointed out that the fairly small sample size is a limitation
of this study. This should be self-explaining. Beside the manuscripts
cited, there are many more rTMS studies presenting data from much smaller
numbers of recruited patients. A paper from the group you are currently
involved, presented data from a sample of 13 actively treated patients.[5] But your letter precisely points out the current difficulties of
rTMS research in depression. TMS is a time consuming therapy requiring a
considerable amount of manpower, which is probably a main reason for the
sample size problems. Given the results of a recent meta-analysis,[6] it
is likely that rTMS has a certain antidepressant effect but not as robust
as thought several years ago. In order to have sufficient statistical
power to detect such effects, considerably larger trials have to be
performed. Multicenter studies are about to be organized throughout Europe
and one study is currently underway. In addition, new stimulation
parameters, overlasting the 2 week stimulation paradigms used till date
might help to enhance antidepressant outcome.[7] This might help to get
out of the current dilemma in rTMS research in depression.
References
1. Connemann BJ. Sufficient power to detect a slight effect? [electronic response to Hausmann et al. No benefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, single centre, randomised, double blind, sham controlled "add on" trial]
jnp.com 2004http://jnnp.bmjjournals.com/cgi/eletters/75/2/320#95
2. Hausmann A, Kemmler G, Walpoth M, et al. No benefit derived from
repetitive transcranial magnetic stimulation in depression: a prospective,
single centre, randomised, double blind, sham controlled "add on" trial. J
Neurol Neurosur Psychiatry 2004;75:320-322.
3. Hausmann A, Pascual-Leone A, Kemmler G, et al. No deterioration of
cognitive performance in an aggressive antidepressant uni- and bilateral
“add-on” rTMS trial. J Clin Psychiatry 2004 in press.
4. Klein E, Kreinin A, Chistyakov A, et al. Therapeutic efficacy of
right prefrontal slow repetitive transcranial magnetic stimulation in
major depression. Arch Gen Psychiatry 1999;56: 315-320.
5. Herwig U, Lampe Y, Juengling FD, et al. Add-on rTMS for tretment
of depression: a pilot study using stereotactic coil-navigation according
to PET data. J Psychiat Res 2003;37:267-275
6. Burt T, Lisanby SH, Sackeim HA (2002) Neuropsychiatric
applications of transcranial magnetic stimulation: a meta analysis. Int J
Neuropsychopharmacol 2002;5:73-103.
7. Fitzgerald PB, Brown TL, Marston NA, Transcranial magnetic
stimulation in the treatment of depression: a double-blind, placebo-
controlled trial. Arch Gen Psychiatry 2003;60:1002-1008.
In their interesting paper Bower and colleagues report results of a
study employing manual amygdala volumetry to imaging-negative patients
with refractory temporal lobe epilepsy (TLE).[1] They identify 7 out of 11
patients in whom they diagnose amygdala enlargement and postulate this
might be attributable to developmental abnormality or low grade tumor.
In their interesting paper Bower and colleagues report results of a
study employing manual amygdala volumetry to imaging-negative patients
with refractory temporal lobe epilepsy (TLE).[1] They identify 7 out of 11
patients in whom they diagnose amygdala enlargement and postulate this
might be attributable to developmental abnormality or low grade tumor.
However, in discussing their interesting observation the authors do not
mention the extensive literature on amygdala enlargement in different
neuropsychiatric conditions. Significant amygdala enlargement has been
reported in patients with unipolar [2] and bipolar depression,[3] and in fact
in patients with refractory TLE and depression and psychosis of
epilepsy.[4,5] Amygdala volumes are increased in first episode major
depression and seem to „normalise“ in the course of the disease.[2]
Finally,
there is some evidence that amygdala volumes might be affected by
psychotropic medication.6 While the mechanism of amygdala enlargement in
all these cases is unknown and open to discussion most of the authors
quoted favour more dynamic mechanisms compared to developmental
abnormalities or tumors. The fact that initial amygdala enlargement seems
to normalise in the course of depression [2] or in case of antipsychotic
medical treatment supports a dynamic underlying mechanism. The fact that
patients with TLE were classified as imaging-negative implies that no
lesional pathology was recognisable on standard MRI investigations.
However, when amygdala enlargement is noted on volumetric findings alone
it is very likely that mechanisms other than developmental abnormalities
or low grade tumours are involved. The investigators should control for
psychiatric morbidity when assessing amygdala volumes. Further more,
Furthermore, one should be very cautious with basing a decision for or
against surgery purely on volumetric findings of the amygdala.
Reference
1. Bower SP, Vogrin SJ, Morris K, et al. Amygdala volumetry in
"imaging-negative" temporal lobe epilepsy. J.Neurol.Neurosurg.Psychiatry
2003;74:1245-9.
2. Frodl T, Meisenzahl EM, Zetzsche T, et al. Larger amygdala
volumes in first depressive episode as compared to recurrent major
depression and healthy control subjects. Biol Psychiatry 2003;53:338-44.
3. Strakowski SM, DeBello MP, Sax KW, et al. Brain magnetic
resonance imaging of structural abnormalities in bipolar disorder. Arch
Gen Psychiatry 1999;56:254-60.
4. Tebartz vE, Woermann FG, Lemieux L, et al. Amygdala enlargement
in dysthymia--a volumetric study of patients with temporal lobe epilepsy.
Biol Psychiatry 1999;46:1614-23.
5. Tebartz vE, Baeumer D, Lemieux L, et al. Amygdala pathology in
psychosis of epilepsy: A magnetic resonance imaging study in patients with
temporal lobe epilepsy. Brain 2002;125:140-9.
6. Tebartz van Elst L, Baeumer D, Ebert D, et al. Chronic
antidopaminergic medication might affect amygdala structure in patients
with schizophrenia. J Clin Psychopharmacology (In Press)
We read with attention the report of Adler and colleagues.[1]
By studying 20 patients with Alzheimer’s
disease (AD) assigned to rivastigmine, the authors found that baseline
short-term memory performances and EEG data are useful for predicting
response to treatment at 6 months.
We would like to contribute to this topic with our own personal data on 24
AD subjects treated for 9 months w...
We read with attention the report of Adler and colleagues.[1]
By studying 20 patients with Alzheimer’s
disease (AD) assigned to rivastigmine, the authors found that baseline
short-term memory performances and EEG data are useful for predicting
response to treatment at 6 months.
We would like to contribute to this topic with our own personal data on 24
AD subjects treated for 9 months with rivastigmine. Subjects were on
average old (mean age = 79.0+5.5 years), predominantly females (n= 16,
65.2%), with a mild cognitive (mean Mini Mental State Examination, MMSE
score =19.5+3.4) and functional (mean number of activities of daily
living, ADL lost = 1.3+1.6) decline. None of them had been previously
treated with other cholinesterase inhibitors or rivastigmine.
As a whole, subjects showed a slight improvement in MMSE score from
baseline to 3 months (mean MMSE score = 19.9+4.4) and the return close to
baseline levels by 9 months (mean MMSE score = 19.4+5.2). However, 9
patients decreased 1 or more MMSE points (non-responders), while 15 did
not change MMSE score or increased 1 or more MMSE points (responders) at 9
months. In order to evaluate whether some specific MMSE items were
predictive of response to treatment at 9 months, the variation of the
scores for each MMSE items from baseline to 3rd month was calculated. In a
stepwise regression model, after adjusting for all potential confounders
(age, gender, duration of disease, and ADL at baseline) and covariates
(total and single items MMSE scores at baseline), the variation at 3rd
month in the score of the MMSE item “delayed recall” was the only
independently and significantly associated with the variation of global
MMSE score at 9th month (B=2.50, 95% confidence intervals 1.28-3.72;
p=.000).
Our data suggest that the variation in a specific MMSE item (i.e. “delayed
recall”) at 3rd month may represent a useful marker of cognitive
improvement at 9th month, indicating that a peculiar neurobiological
structure, responsible of a selective neuropsychological domain, should be
a preferential target of rivastigmine therapeutic action.
References
1. Adler G, Brassen S, Chwalek K, Dieter B and Teufel M. Prediction of
treatment response to rivastigmine in Alzheimer’s dementia. J Neurol
Neurosurg Psychiatry 2004; 75:292-294.
Dear Editor
In their very interesting paper on the assessment of personality in patients with epileptic (ES) and psychogenic non-epileptic seizures (PNES) Reuber and colleagues conclude that maladaptive personality in patients with PNES is common, reminiscent of Borderline Personality Disorder (BPD) in a large subgroup and can be distinguished from non-clinical controls and patients with epilepsy alone.[1]
H...
Dear Editor
Benzodiazepines are now the most prescribed group of psychoactive drugs, and their safety for therapeutic use has been established, but there also is the potential for abuse and addiction.[1]
Endozepine stupor (ES) is characterized by repeated, spontaneous stuporous attacks lasting several hours or days, and responsiveness to flumazenil without administration of benzodiazepine. ES is caused by...
Dear Editor
We greatly appreciate the considerable and thoughtful comments offered by Boris Kotchoubey and his interest in our report of three cases in a persistent vegetative state (PVS) after severe head injury, who recovered from a prolonged disturbance of consciousness after the administration of levodopa.[1]
As author points it out, PVS patient present a wide range of neurological symptoms and syndro...
Dear Editor
The Short Report by Ago and colleagues,[1] describing deterioration of pre-existing left hemiparesis by a subsequent ipsilateral hemispheric insult, contains a laterality-indexed aspect related to motor control in humans, not addressed by the authors.
Cases similar to their patient are on record.[2] The explanation of the laterality indexed bilateral activation of motor cortices (or, as in...
Dear Editor
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All three patients had parkinsonian symptoms and MRI evidence of the damage to the substantia nigra or ventral tegmental area. This is an astonishing r...
Dear Editor
Regarding Ginsberg's article: Difficult and recurrent.[1]
The rationale underlying the author's use of a frequent dosing regimen for antibiotics in acute bacterial meningitis is a sound one, namely to compensate for the eventuality of missed doses,[1] the latter being one of the realities in a service tightly stretched for manpower. The unequivocal recommendation for a 4-hour dosing regime f...
Dear Editpor
I read with interest that Wilson et al.[1] have confirmed an association between depressive symptoms and subsequent cognitive decline in a large defined community followed prospectively for an average of 5.3 years. The various possible explanations were discussed by Stewart.[2]
I wish to draw attention to one possible biological model of the risk factor or prodromal interpretation of th...
Dear Editor
In reply to the comments by Dr Connemann [1]:
Although our study was designed to investigate rTMS add-on effects in an aggressive stimulation paradigm [2] we did not find a significant difference between the active group (n= 25) in comparison to sham (n=13) in a two week trial. Although we used aggressive parameters in an add-on setting neurocognitive measure even slightly improved in the acti...
Dear Editor
In their interesting paper Bower and colleagues report results of a study employing manual amygdala volumetry to imaging-negative patients with refractory temporal lobe epilepsy (TLE).[1] They identify 7 out of 11 patients in whom they diagnose amygdala enlargement and postulate this might be attributable to developmental abnormality or low grade tumor.
However, in discussing their interesting o...
Dear Editor
We read with attention the report of Adler and colleagues.[1]
By studying 20 patients with Alzheimer’s disease (AD) assigned to rivastigmine, the authors found that baseline short-term memory performances and EEG data are useful for predicting response to treatment at 6 months.
We would like to contribute to this topic with our own personal data on 24 AD subjects treated for 9 months w...
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