Journal of the Royal Society of Medicine Volume 83 April 1990 but he cannot be investigated fully at every attendance. Any investigation in patients who are HIV positive are, by definition, kept to a minimum, particularly when they involve blood tests and endoscopy. It is therefore possible that a patient with Munchausen's can prolong his stay in hospital simply by informing the admitting doctor that he is HIV positive. This patient was a significant hazard to staff. He was actively bleeding and took no precautions to contain the blood. On this admission he was known to be HIV positive but at all his medical consultations the following week, he failed to reveal this fact. This case suggests the need for a register of patients who are HIV positive and have Munchausen's syndrome in order to protect hospital staff but the practicalities of absolute
Parkinsonian tremor and Waldenstrom's macroglobulinaemia
S MacRury Ms chB mRcP'
R Watkins MD mRCPath2
K R Paterson MB ChB MRCP1 'Medical Unit and 2Department of Haematology, Royal Infirmary, Glasgow 04 OSF
confidentiality, at present, prevent this. This case also emphasizes the importance of taking simple precautions to avoid contact with blood in all patients and not only those known to be at high risk. References 1 Robinson EN, Latham RH. A factitious case of acquired immuno deficiency syndrome. Sexually Transmitted Diseases 1987;1:&4-7 2 Miller F, Weiden P, Sachs M, Wozniak J. Two cases of factitious acquired immuno-deficiency syndrome (letter). Am J Psychiatry 1986;143:1483 3 Asher R. Munchausen syndrome. Lancet 1951;i:339-41
(Accepted 10 February 1989)
IgM (g/1)
A syndrome of hyperglobulinaemia and central nervous system affection was first described by Bing and Neel in 19361, but Waldenstrom's macroglobulinaemia, a condition of plasma and lymphoid cell proliferation resulting in IgM paraproteinaemia and diffuse plasmalymphoid infiltrates, was not described until 19442. Central nervous system involvement (Bing-Neel syndrome) has been found in about 25% of patients with macroglobulinaemia and usually presents as stroke, encephalopathy, myelopathy or peripheral neuropathy3. We report on a patient who presented initially with an isolated extrapyramidal lesion and was subsequently found to have macroglobulinaemia. Case report A 56-year-old seaman presented with sudden onsit bilateral tremor of the hands at rest which had remained unchanged for the last 10 weeks. He had a past history of alcohol abuse, but had abstained for the previous 6 years. Peripheral sensory neuropathy had been diagnosed 5 years previously. On examination, there was a Parkinsonian tremor (frequency 6 hz), with typical 'pill-rolling' action at rest in both hands. Tone was normal, there was no bradykinesia and a negative glabellar tap. There was evidence of peripheral neuropathy with reduced cutaneous sensation over both feet, absent vibration sense and absent ankle reflexes in the lower limbs; Examination of the fukidi was normal and no other abnormal physical signs were detected. Initial investigations showed normochromic normocytic anaemia (Hb 10.6 g/dl) and a raised erythrocyte sedimentation rate (123 mm/hr).. Thyroid function, serum caeruloplasmin, urinary copper excretion, CAT scan ofhead and electroencephalogram were all normal. Subsequent investigations showed reduced serum albumin (29 g/l; normal 35-55 gll) and raised serum globulin (82 gll; normal 22-33 gIl). The plasma IgM level was raised (76 g/l; normal 0.3-4 gIl), IgG and IgA levels were normal and there were no cryoglobulins. Marrow aspirate showed a dense infiltrate of small mature lymphocytes and plasma cells confirming
Plasma viscosity
-
f
Chlorambucil
s5
(cp)
90-
V
50-
"vs Plasma viscosity
30 -_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_- ----Norrrwl range Upper lmit 1
20
10^ NormaIrange - -
Keywords: macroglobulinaemia; tremor
273
-
t On
t
t
2
15
adtission
t t1 2 2 .1-5
2t 15
3 t1 t2 4 25L t weeks
Figure 1. Changes in plasma viscosity and IgM levels with plasmapheresis and chemotherapy over initial 4 weeks of treatment
the diagnosis of Waldenstrom's macroglobulinaemia. Plasma viscosity was markedly raised at 4.006 cp (normal 1.45 cp, 370C) and treatment was started with plasmapheresis (total of 16 litres exchanged), and chlorambucil 5 mg/day. While immunoglobulin and viscosity levels fell progressively (Figure 1), the tremor remained unchanged, but no further signs of basal ganglia disease developed.
Discussion The manifestations of Waldenstrom's macroglobulinaemia are due to two pathological processes: (i) IgM is a large, mainly intravascular, molecule which in excess increases red cell aggregation and plasma viscosity. This results in reduced blood flow causing vascular stasis, occlusion and ischaemia and a bleeding tendency due to interference with coagulation factors and platelet function; (ii) plasma and lymphoid cellular infiltrates may result in tumour masses resembling lymphoma or chronic lymphatic leukaemia. The mechanism of the neurological involvement is attributed to various pathologies. Strokes and encephalopathies have improved-following plasmapheresis suggesting that reduced cerebral perfusion due to hyperviscosity was responsible4. Some of the central effects may be due to haemorrhage or infarction and peripheral effects to ischaemia from red cell agglutination in the vasa nervorum5 or deposition of IgM in myelin sheaths6. In the case reported here, the sudden onset and nature of the tremor suggests a small infarct or haemorrhage in the basal ganglia region, although no structural lesion was visualized and there were no other haemorrhagic manifestations. Failure of the tremor to improve despite treatment of hyperviscosity also supports a more permanent lesion. Previously gross tremor of both hands in a patient with Waldenstrom's macroglobulinaemiahas been descibed, but with no obvious Parkinsonian features7. The cause of the peripheral neuropathy remains obscure; it is atypical
0141-0768/90/
040273-02/$02.00/0 © 1990
The Royal Society of Medicine
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Journal of the Royal Society of Medicine Volume 83 April 1990
of the Bing-Neel syndrome since it had been documented for at least 5 years before diagnosis of macroglobulinaemia, although a previous case has been reported where neuropathy was present four years before macroglobulinaemia was diagnosed8. It remains possible that it was secondary to longstanding alcohol abuse. This patient's presentation of macroglobulinaemia with a single manifestation of basal ganglia disease is rare. We would suggest that it is worthwhile checking serum proteins in any middle-aged or elderly patient with unusual central nervous system signs and/or peripheral neuropathy when other causes have been excluded. Acknowledgment: We would like to thank Dr J Goodall for allowing us to report on his patient and Dr G D 0 Lowe for performing the viscosity analysis. References 1 Bing J, Neel AV. Two cases of hyperglobulinaemia with affection of the central nervous system on a toxi-infectious basis. Acta Med Scand 1936;88:492-506
2 Waldenstrom J. Incipient myelomatosis, or "essential" fibrinogenopenia - a new syndrome? Acta Med Scand 1944;117: 216 13 Logothetis J, Silverstein P, Coe J. Neurological aspects of Waldenstrom's macroglobulinaemia. Arch Neurol 1960;5: 564-73 4 Solomon A. Neurological manifestations of macroglobulinaemia. In: Brain L, Norris R, eds. The remote effects of cancer on the nervous system. New York: Grune & 'Stratton, 1965: 112-24 5 Edgar R, Dutcher TF. Histopathology of the Bing-Neel syndrome. Neurology 1961;11:239-45 6 Julien J, Vital C, Vallat JM, Lagueny A, Deminiere C, Darriet D. Polyneuropathy in Waldenstrom's macroglobulinaemia. Arch Neurol 1978;35:423-4 7 MacKay IR, Taft LI, Wood EF. Clinical features and pathogenesis of macroglobulinaemia. Br Med J 1978;i:561-3 8 Spencer SS, Moench JC. Progressive and treatable cerebellar ataxia in macroglobulinaemia. Neurology 1978;30:536-8
(Accepted 16 February 1989)
Meeting report
The anxiolytic jungle: where next? Keywords: anxiolytics; benzodiazepine; cognitive impairment; betablockers; hypnotics
The anxiogenic jungle of modern civilization produces many varied and persisting stresses, that create anxiety in many people. Should we use anxiolytic drugs to help them survive when their coping mechanisms fail? Or should we use a non-drug approach? The meeting addressed itself to these problems and a number of distinguished speakers covered differing aspects of the subject. The diverse uses of benzodiazepines (BDZs) in clinical practice were considered by Michael Trimble (National Hospital for Nervous Diseases) who emphasized that any equation of BDZs with anxiety is misleading since these drugs have myorelaxant, anticonvulsant, sedative and amnesic, properties, all of which have been used for their clinical effects. For example, the 1,5 BDZ clobazam is a broad-spectrum anticonvulsant used as adjunctive therapy-in epilepsy; whilst spasticity and dystonic syndromes variably respond to the muscle relaxant properties of the BDZs. They have been used as amnesic agents prior to surgery and also have potential use in affective disorders such as, for example, mania BDZs with short elimination half-lives can be recommended as hypnotics and also in severe anxiety unresponsive to behavioural treatments and in trauma-induced acute anxiety. Dr Peter Tyrer (St Charles Hospital, London) emphasized that BDZ use is still over-shadowed by the risks of dependence and tis dwarfs all other problems posed by these drugs. Recent research has been directed -towards better identification of the factors predisposing to dependence: dosage, duration
of treatment, type of BDZ and personality status of the consumers. Against the dangers of dependence must be balanced the relative merits of long-term use in: panic disorder, recurring neurotic symptomatology and intermittent alcohol abuse. Other problems are the type and extent of cognitive and sensorimotor impairment, lack of efficacy after repeated dosage and illegal use of BDZs.
Based on,meeting of Forum on Clinical Pharmacology & Therapeutics, 6 October 1989
Many of the problems with the BDZs are related to the pharmacokinetics of the different compounds and Robin Braithwaite (Regional Laboratory for Toxicology, Birmingham) described the development and introduction of new more potent BDZ hypnotics with;a rapid onset of action, fast rate of elimination and minimal residual effects. Simple differences in the pl drug concentration-time curve do not fully explain differences in the duration of clinical action and the rate of passage to and from the CSF and brain, together with interaction with-BDZ receptor sites, are important factors. The pharmacokinetic properties of some BDZs are more likely to create dependence problems whereas others lend themselves to the management of BDZ- withdrawal. Conitive impairment with the BDZs was. considered by Ia n dmarch (Department of Psychology, University-of Leeds) who suggested that the effects of a tranquiUizer might be likened to being 'wrapped in emotional cotton wool'. However, not all compounds are the same, as illustrated by a trial of clobazam compared with lorazepam; the anxiolytic effects were the same bit short-term memory was impaired by the latter but not by the former. In another study comparig clobazam with clorazepafe, there was a return of anxiety after stoppi?tg the clorazepate but relief of 0141-0768/90/ anxiety was maintained after stopping clobazam. In 040274-02402.00/0 a further study of clobazam againt bromazepam, the o 1990 latter was ineffective in relieving anxiety. The Royal On cognitive driving tests clobazam showed no Society of adverse effects whereas lorazepam caused considerable Medicine
Parkinsonian tremor and Waldenstrom's macroglobulinaemia
S MacRury Ms chB mRcP'
R Watkins MD mRCPath2
K R Paterson MB ChB MRCP1 'Medical Unit and 2Department of Haematology, Royal Infirmary, Glasgow 04 OSF
confidentiality, at present, prevent this. This case also emphasizes the importance of taking simple precautions to avoid contact with blood in all patients and not only those known to be at high risk. References 1 Robinson EN, Latham RH. A factitious case of acquired immuno deficiency syndrome. Sexually Transmitted Diseases 1987;1:&4-7 2 Miller F, Weiden P, Sachs M, Wozniak J. Two cases of factitious acquired immuno-deficiency syndrome (letter). Am J Psychiatry 1986;143:1483 3 Asher R. Munchausen syndrome. Lancet 1951;i:339-41
(Accepted 10 February 1989)
IgM (g/1)
A syndrome of hyperglobulinaemia and central nervous system affection was first described by Bing and Neel in 19361, but Waldenstrom's macroglobulinaemia, a condition of plasma and lymphoid cell proliferation resulting in IgM paraproteinaemia and diffuse plasmalymphoid infiltrates, was not described until 19442. Central nervous system involvement (Bing-Neel syndrome) has been found in about 25% of patients with macroglobulinaemia and usually presents as stroke, encephalopathy, myelopathy or peripheral neuropathy3. We report on a patient who presented initially with an isolated extrapyramidal lesion and was subsequently found to have macroglobulinaemia. Case report A 56-year-old seaman presented with sudden onsit bilateral tremor of the hands at rest which had remained unchanged for the last 10 weeks. He had a past history of alcohol abuse, but had abstained for the previous 6 years. Peripheral sensory neuropathy had been diagnosed 5 years previously. On examination, there was a Parkinsonian tremor (frequency 6 hz), with typical 'pill-rolling' action at rest in both hands. Tone was normal, there was no bradykinesia and a negative glabellar tap. There was evidence of peripheral neuropathy with reduced cutaneous sensation over both feet, absent vibration sense and absent ankle reflexes in the lower limbs; Examination of the fukidi was normal and no other abnormal physical signs were detected. Initial investigations showed normochromic normocytic anaemia (Hb 10.6 g/dl) and a raised erythrocyte sedimentation rate (123 mm/hr).. Thyroid function, serum caeruloplasmin, urinary copper excretion, CAT scan ofhead and electroencephalogram were all normal. Subsequent investigations showed reduced serum albumin (29 g/l; normal 35-55 gll) and raised serum globulin (82 gll; normal 22-33 gIl). The plasma IgM level was raised (76 g/l; normal 0.3-4 gIl), IgG and IgA levels were normal and there were no cryoglobulins. Marrow aspirate showed a dense infiltrate of small mature lymphocytes and plasma cells confirming
Plasma viscosity
-
f
Chlorambucil
s5
(cp)
90-
V
50-
"vs Plasma viscosity
30 -_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_- ----Norrrwl range Upper lmit 1
20
10^ NormaIrange - -
Keywords: macroglobulinaemia; tremor
273
-
t On
t
t
2
15
adtission
t t1 2 2 .1-5
2t 15
3 t1 t2 4 25L t weeks
Figure 1. Changes in plasma viscosity and IgM levels with plasmapheresis and chemotherapy over initial 4 weeks of treatment
the diagnosis of Waldenstrom's macroglobulinaemia. Plasma viscosity was markedly raised at 4.006 cp (normal 1.45 cp, 370C) and treatment was started with plasmapheresis (total of 16 litres exchanged), and chlorambucil 5 mg/day. While immunoglobulin and viscosity levels fell progressively (Figure 1), the tremor remained unchanged, but no further signs of basal ganglia disease developed.
Discussion The manifestations of Waldenstrom's macroglobulinaemia are due to two pathological processes: (i) IgM is a large, mainly intravascular, molecule which in excess increases red cell aggregation and plasma viscosity. This results in reduced blood flow causing vascular stasis, occlusion and ischaemia and a bleeding tendency due to interference with coagulation factors and platelet function; (ii) plasma and lymphoid cellular infiltrates may result in tumour masses resembling lymphoma or chronic lymphatic leukaemia. The mechanism of the neurological involvement is attributed to various pathologies. Strokes and encephalopathies have improved-following plasmapheresis suggesting that reduced cerebral perfusion due to hyperviscosity was responsible4. Some of the central effects may be due to haemorrhage or infarction and peripheral effects to ischaemia from red cell agglutination in the vasa nervorum5 or deposition of IgM in myelin sheaths6. In the case reported here, the sudden onset and nature of the tremor suggests a small infarct or haemorrhage in the basal ganglia region, although no structural lesion was visualized and there were no other haemorrhagic manifestations. Failure of the tremor to improve despite treatment of hyperviscosity also supports a more permanent lesion. Previously gross tremor of both hands in a patient with Waldenstrom's macroglobulinaemiahas been descibed, but with no obvious Parkinsonian features7. The cause of the peripheral neuropathy remains obscure; it is atypical
0141-0768/90/
040273-02/$02.00/0 © 1990
The Royal Society of Medicine
274
Journal of the Royal Society of Medicine Volume 83 April 1990
of the Bing-Neel syndrome since it had been documented for at least 5 years before diagnosis of macroglobulinaemia, although a previous case has been reported where neuropathy was present four years before macroglobulinaemia was diagnosed8. It remains possible that it was secondary to longstanding alcohol abuse. This patient's presentation of macroglobulinaemia with a single manifestation of basal ganglia disease is rare. We would suggest that it is worthwhile checking serum proteins in any middle-aged or elderly patient with unusual central nervous system signs and/or peripheral neuropathy when other causes have been excluded. Acknowledgment: We would like to thank Dr J Goodall for allowing us to report on his patient and Dr G D 0 Lowe for performing the viscosity analysis. References 1 Bing J, Neel AV. Two cases of hyperglobulinaemia with affection of the central nervous system on a toxi-infectious basis. Acta Med Scand 1936;88:492-506
2 Waldenstrom J. Incipient myelomatosis, or "essential" fibrinogenopenia - a new syndrome? Acta Med Scand 1944;117: 216 13 Logothetis J, Silverstein P, Coe J. Neurological aspects of Waldenstrom's macroglobulinaemia. Arch Neurol 1960;5: 564-73 4 Solomon A. Neurological manifestations of macroglobulinaemia. In: Brain L, Norris R, eds. The remote effects of cancer on the nervous system. New York: Grune & 'Stratton, 1965: 112-24 5 Edgar R, Dutcher TF. Histopathology of the Bing-Neel syndrome. Neurology 1961;11:239-45 6 Julien J, Vital C, Vallat JM, Lagueny A, Deminiere C, Darriet D. Polyneuropathy in Waldenstrom's macroglobulinaemia. Arch Neurol 1978;35:423-4 7 MacKay IR, Taft LI, Wood EF. Clinical features and pathogenesis of macroglobulinaemia. Br Med J 1978;i:561-3 8 Spencer SS, Moench JC. Progressive and treatable cerebellar ataxia in macroglobulinaemia. Neurology 1978;30:536-8
(Accepted 16 February 1989)
Meeting report
The anxiolytic jungle: where next? Keywords: anxiolytics; benzodiazepine; cognitive impairment; betablockers; hypnotics
The anxiogenic jungle of modern civilization produces many varied and persisting stresses, that create anxiety in many people. Should we use anxiolytic drugs to help them survive when their coping mechanisms fail? Or should we use a non-drug approach? The meeting addressed itself to these problems and a number of distinguished speakers covered differing aspects of the subject. The diverse uses of benzodiazepines (BDZs) in clinical practice were considered by Michael Trimble (National Hospital for Nervous Diseases) who emphasized that any equation of BDZs with anxiety is misleading since these drugs have myorelaxant, anticonvulsant, sedative and amnesic, properties, all of which have been used for their clinical effects. For example, the 1,5 BDZ clobazam is a broad-spectrum anticonvulsant used as adjunctive therapy-in epilepsy; whilst spasticity and dystonic syndromes variably respond to the muscle relaxant properties of the BDZs. They have been used as amnesic agents prior to surgery and also have potential use in affective disorders such as, for example, mania BDZs with short elimination half-lives can be recommended as hypnotics and also in severe anxiety unresponsive to behavioural treatments and in trauma-induced acute anxiety. Dr Peter Tyrer (St Charles Hospital, London) emphasized that BDZ use is still over-shadowed by the risks of dependence and tis dwarfs all other problems posed by these drugs. Recent research has been directed -towards better identification of the factors predisposing to dependence: dosage, duration
of treatment, type of BDZ and personality status of the consumers. Against the dangers of dependence must be balanced the relative merits of long-term use in: panic disorder, recurring neurotic symptomatology and intermittent alcohol abuse. Other problems are the type and extent of cognitive and sensorimotor impairment, lack of efficacy after repeated dosage and illegal use of BDZs.
Based on,meeting of Forum on Clinical Pharmacology & Therapeutics, 6 October 1989
Many of the problems with the BDZs are related to the pharmacokinetics of the different compounds and Robin Braithwaite (Regional Laboratory for Toxicology, Birmingham) described the development and introduction of new more potent BDZ hypnotics with;a rapid onset of action, fast rate of elimination and minimal residual effects. Simple differences in the pl drug concentration-time curve do not fully explain differences in the duration of clinical action and the rate of passage to and from the CSF and brain, together with interaction with-BDZ receptor sites, are important factors. The pharmacokinetic properties of some BDZs are more likely to create dependence problems whereas others lend themselves to the management of BDZ- withdrawal. Conitive impairment with the BDZs was. considered by Ia n dmarch (Department of Psychology, University-of Leeds) who suggested that the effects of a tranquiUizer might be likened to being 'wrapped in emotional cotton wool'. However, not all compounds are the same, as illustrated by a trial of clobazam compared with lorazepam; the anxiolytic effects were the same bit short-term memory was impaired by the latter but not by the former. In another study comparig clobazam with clorazepafe, there was a return of anxiety after stoppi?tg the clorazepate but relief of 0141-0768/90/ anxiety was maintained after stopping clobazam. In 040274-02402.00/0 a further study of clobazam againt bromazepam, the o 1990 latter was ineffective in relieving anxiety. The Royal On cognitive driving tests clobazam showed no Society of adverse effects whereas lorazepam caused considerable Medicine
