408 Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:408–416 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from

A 45 year old man presented with a three single strand conformation polymorphism month history of progressive memory deficit, analysis did not detect any mutations in the LETTERS TO listlessness, and loss of speech. He repeatedly coding sequence of the prion protein (PrP) lost his orientation in the forest where he had gene. At residue 129 the patient was ho- THE EDITOR worked as a wood cutter for many years. His mozygous for valine. history was remarkable for bulbectomy of the Two months after onset of clinical symp- right eye at the age of 15 months, probably toms MRI was performed. T1 weighted due to retinoblastoma. On examination he images before and after infusion of a contrast complied with simple requests, only. He agent were normal, whereas on T2 and Magnetic resonance imaging in spoke very little with multiple perseverations. proton density weighted images the left fron- Creutzfeldt-Jakob disease: evidence of Severe deficits of memory and orientation tal cortex appeared thicker and returned a focal involvement of the cortex were obvious. Pronounced irritability with higher signal than the other hemisphere (fig- bursts of aggressiveness made neuroleptic ure). However, when using a FLAIR se- therapy necessary. Deep tendon reflexes were quence the patchy hyperintense signal of the Creutzfeldt-Jakob disease is a prion disease brisk but plantar responses were flexor. cortical layer was more apparent. clinically characterised by rapidly progressing Rigidity aVecting all limbs and hypomimia An open brain biopsy of the left frontal lobe dementia, cerebellar and extrapyramidal indicated involvement of the extrapyramidal was performed. Histopathological examin- signs, and myoclonus. Cerebral imaging pro- system. On walking the right arm did not ation disclosed spongiform changes of the cer- cedures are considered to be of little value for swing. The gait was broad based and fixation ebral cortex, loss of neurons and astrogliosis, definite premortem diagnosis, which still did not suppress the oculocephalic reflex but no inflammatory infiltrates. A diagnosis of depends on brain biopsy. Corresponding to suggesting cerebellar involvement. Serial spongiform encephalopathy (Creutzfeldt- cognitive deficits neuropathological changes electric ECG recordings disclosed a progres- Jakob disease) was made based on typical mostly aVect the cerebral cortex, and less sive general slowing and a left frontotempo- pathological changes. Immunhistochemistry severely other grey matter areas such as the ral, non-periodic slow wave activity. Cerebro- showed no PrP deposits. caudate, putamen, and thalamus.1 The fol- spinal fluid cell count and protein On follow up, the patient continued to lowing case report suggests that MRI using a composition were normal. Caeruloplasmin deteriorate. Eight months after onset of fluid attenuated inversion recovery (FLAIR) and urinary copper concentrations were symptoms he was reported to be completely sequence might detect pathological changes within the normal range. In accordance with unresponsive. At that time myocloni of the in the cerebral cortex. a negative family history for prion disease a arms were seen. He died 16 months after onset of symptoms. At necropsy the brain showed pronounced frontal cortical atrophy. The ventricular system was enlarged and atrophy of the cau- date nucleus was seen. No cerebellar atrophy was detectable. Histology showed severe spongiform degeneration, severe gliosis, and nerve cell loss in the cerebral cortex. Severe changes were also found in the putamen and to a lesser extent in the thalamus. In the cer- copyright. ebellum only mild spongiform changes in the molecular layer were seen. The granular cell layer seemed unaVected. Immunhistochemis- try was performed using the antibodies Gö138 and 3F4. As in the brain biopsy no prion protein deposits were detectable in the neocortex or cerebellum. In western blot analysis, proteinase K resistant prion protein was found. This patient presented with the clinical features of Creutzfeldt-Jakob disease. Diag- nosis of spongiform encephalopathy was confirmed by brain biopsy. Whereas T1 http://jnnp.bmj.com/ weighted MRI was normal, and T2 and PD weighted images showed only subtle findings, a cortical hyperintensity could be easily seen on FLAIR images. This hyperintensity pre- dominantly aVected the left frontal, insular, and parietal cortex; the right frontal cortex was also involved (figure). Findings in MRI have been reported in several cases of patho-

logically established Creutzfeldt-Jakob dis- on September 24, 2021 by guest. Protected ease. Brain MRI might be normal or show either brain atrophy or symmetric, hyperin- tense signals of the basal ganglia in T2 weighted images.23 Occasionally, hyperintense signals of the cerebral cortex have been reported.2 The low incidence of cortical involvement reported on MRI contradicts neuropathological data. In a MRI (courtesy of the Centre Hospitalier series of 21 necropsied cases, the cortex was Luxembourg). (A) fluid attenuated inversion the earliest and most severely involved by recovery (FLAIR) sequence with spongiform changes.1 The basis of this 10002/164/2600 TR/TE/TI with 5 mm slice discrepancy may be that on conventional T2 thickness on 1.5 T Signa shows increased signal weighted MRI the high intensity of CSF of left frontal, posterior temporal, parietal, and occipital gyri without tissue swelling (arrows); interferes with a sensitive display of cortical (B) with T2 (4000/95 TR/TEef); (C) proton signal. density (4000/19 TR/TEef) weighted fast spin To our knowledge, application of the echo sequences, cortical widening is evident. The FLAIR sequence in Creutzfeldt-Jakob dis- extent of cortical involvement, however, is ease has not been reported so far. The FLAIR diYcult to detect without knowledge of the sequence is a heavily weighted inversion FLAIR sequence. recovery sequence with an inversion time Letters, Book reviews 409 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from designed to null the CSF signal but allow Primary central nervous system titres against Epstein-Barr virus were also recovery of most of the brain magnetisation. lymphoma presenting with multiple negative in both serum and CSF samples. Slit This sequence reduces the CSF artefact and myeloma-like clinical picture lamp examination was normal, with no enhances contrast of pathology at the surface lymphomononuclear deposits in the uvea or of the brain or adjacent to the ventricles. Primary cerebral lymphoma is a unique and vitreous fluid. Staging procedures including There was a left frontotemporal accentua- infrequent CNS malignancy in which the B CT of the abdomen and pelvis, bilateral bone tion of the hyperintense changes of the cortex lymphocyte subtype constitutes most cases.1 marrow aspiration, and biopsies were within in our patient. A focal involvement of the cor- B cell neoplasms other than multiple my- normal limits precluding the diagnosis of pri- tex has been reported as an early neuropatho- eloma including non-Hodgkin’s lymphomas, mary cerebral lymphoma. She received 4920 4 logical finding in Creutzfeldt-Jakob disease. and acute and chronic leukaemias might also cGy radiotherapy to the whole cranium Experimental data suggest that the infectious exhibit lytic bone lesions, hypercalcaemia, followed by COPP (cyclophosphamide, vinc- process begins focally and spreads via an ristine, procarbazine and prednisone) chemo- 5 and monoclonal gammopathy via the particu- axonal trans-synaptic pathway. Spread of the lar actions of interleukin (IL-1), IL-6, or therapy, repeated every fourth week. By the infectious agent via commissural pathways to tumour necrosis factor-á secreted by the third month of follow up, serum and CSF the contralateral cortex could explain the neoplastic B cell clone, but not reported pre- paraprotein disappeared and lytic skull le- partially symmetric distribution of the hyper- viously secondary to a primary cerebral sions regressed. Concurrent cranium MRI intense signal seen in our case. lymphoma.2 We describe an unusual presen- disclosed no residual or recurrent mass and The present case suggests that MRI using tation of a B cell primary cerebral lymphoma repeated investigation for systemic FLAIR sequences may be helpful in the diag- mimicking a plasma cell dyscrasia. lymphoma was also negative. She is still being nosis of Creutzfeldt-Jakob disease antemor- A 64 year old woman was admitted with followed up and has so far survived more than tem and provides a tool for characterising the complaints of headache, ataxia, and urinary a year. pathological process in cases of Creutzfeldt- incontinence. Physical examination disclosed Despite the diVerences in localisation and Jakob disease. motor dysfunction in the legs, dysphasia, and biology, non-Hodgkin’s lymphomas arising MARKUS SCHWANINGER impaired cerebellar function. On initial evalu- from the CNS are not histologically diVerent RALF WINTER ation, a mass of 6×4 cm in diameter was from the ones arising at extraneural sites, WERNER HACKE shown in the left frontal lobe by MRI of the except that almost all have intermediate or Department of Neurology high grade histology, predominantly of B cell cranium (fig 1). Haematological and blood 4 RÜDIGER VON KUMMER biochemistry values were within normal lim- subtype. The monoclonality of intracellular Department of Neuroradiology its. Direct skull radiography disclosed multi- immunoglobulins and cell lines obtained ple lytic lesions (fig 2). Serum immunoglobu- from primary cerebral lymphoma tissue CLEMENS SOMMER cultures is well established.5 These specific MARIKA KIESSLING lin (Ig) G concentration was high (3400 clonal products might be detected in CSF but Department of Neuropathology, University of mg/dl; normal<1800) and a monoclonal pro- Heidelberg, Heidelberg, Germany tein band of IgG-ê type was detected by not reflected in systemic circulation probably immunoelectrophoresis. Total excision of the owing to the presence of an intact blood- WALTER J SCHULZ-SCHAEFFER brain barrier that, to the our knowledge, a B HANS A KRETZSCHMAR lesion disclosed large lymphocytes with oval cell primary cerebral lymphoma with raised Department of Neuropathology, University of and vesicular nuclei, and prominent nucleoli Göttingen, Germany consistent with “intermediate grade large cell serum monoclonal paraprotein and lytic skull lesions simulating multiple myeloma has not Correspondence to: Dr Markus Schwaninger, malignant lymphoma” according to the copyright. Department of Neurology, Im Neuenheimer Feld working formulation.3 Methyl green pyronine been previously reported. The probable 400, 69120 Heidelberg, Germany. stain was positive indicating cytoplasmic factors of disturbed blood-brain barrier, RNA accumulation and lymphoplasmocytoid tumorous penetration of vascular spaces, or diVerentiation. Staining with CD10 was also stimulation of angiogenetic collateral forma- 1 Masters CL, Richardson EP Jr. Subacute positive confirming the diagnosis of B cell tion secondary to neoplastic outgrowth might spongiform encephalopathy (Creutzfeldt-Jakob lymphoma. The tumour margins showed be, alone or in combination, responsible for disease). The nature and progression of spongi- those remote eVects of primary cerebral form change. Brain 1978;101:333–44. infiltration into the surrounding white matter 2 Gertz H-J, Henkes H, Cervos-Navarro J. and extending to perivascular spaces with lymphoma. This remains to be verified. The Creutzfeldt-Jakob disease: correlation of MRI absence of involvement of subarachnoid contradictory pattern of overlapping symp- and neuropathological findings. Neurology tomatology of B cell neoplasms makes it 1988;38:1481–2. spaces, dura, or bony structures. Pathological 3 Esmonde TFG, Will RG. Magnetic resonance examination of the largest lytic skull lesion obligatory to achieve the definitive his- imaging in Creutzfeldt-Jakob disease. Ann disclosed “osteolysis without a neoplastic topathological diagnosis particularly in the Neurol 1992;31:230–1. infiltration”. Immunoelectrophoresis of CSF case of primary cerebral lymphoma , in which 4 Heye N, Henkes H, Hansen M-L, Gosztonyi G. the therapeutic algorithm as well as the prog- Focal-unilateral accentuation of changes ob- showed a monoclonal IgG-ê band similar to http://jnnp.bmj.com/ served in the early stages of Creutzfeldt-Jakob the results of serum assays whereas biochemi- nosis have diverse features. disease. J Neurol Sci 1990;95:105–10. cal and cytopathological CSF examinations ISMAIL ÇELIK 5 Fraser H. Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal were normal. Enzyme linked immunosorbent NESLIHAN BASÇIL pathway. Nature 1982;295:149–50. assay (ELISA) tests for HIV and antibody IBRAHIM BARISTA IBRAHIM GÜLLÜ on September 24, 2021 by guest. Protected

Figure 2 Direct lateral radiography of the skull of the patient, showing multiple punched out Figure 1 MRI of cranium showing a mass of 6×4 cm in diameter, located in the left frontotemporal lytic lesions of the cranial vault, with no lobe, showing moderate enhancement after intravenous contrast material injection. evidence of a periosteal reaction. 410 Letters, Book reviews J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from

GÜLTEN TEKUZMAN was inserted. Subsequently the syrinx col- J VAN GIJN DINÇER FIRAT lapsed, but the attacks of pain continued PCLMGIESBERGEN Department of Medical Oncology, Hacettepe unabated. Examination (in 1996) showed T U HOOGENRAAD University Institute of Oncology, Ankara, Turkey normal power and sensation in the arms, a University Department of Neurology, Utrecht, Correspondence to: Dr Ismail Çelik, Hacettepe thoracic kyphosis, and on the left side of the The Netherlands University Institute of Oncology, Department of trunk a suspended level of hypaesthesia and Correspondence to: Professor J van Gijn, University Medical Oncology, 06100 Sihhiye, Ankara, Turkey. hypalgesia, extending from just under the Department of Neurology, University Hospital, PO nipple down to the left leg, as far as 10 cm Box 85500, 3508 GA Utrecht, The Netherlands. 1 Hochberg F, Miller DC. Primary central below the knee; vibration sense was abolished nervous system lymphoma. J Neurosurg below the sternum on both sides. Power in 1988;68:835–53. 1 Vanneste JAL, Van der Bent M. Leg pain 2 Rossi JF, Chappard D, Marcelli C, Laplante J, the legs was normal; the tendon jerks were following syringomyelia of conus medullaris. Commes T, Baldet P, et al. Micro-osteoclast very brisk on the right and sluggish on the Spine 1990;15:434–6. resorption as a characteristic feature of B-cell left, both plantar responses flexor. Repeated 2 Steel TR, Botterill P, Sheehy JP. Paraganglioma malignancies other than multiple myeloma. Br of the cauda equina with associated J Haematol 1990;76:469–75. MRI studies confirmed a collapsed syrinx in syringomyelia: case report. Surg Neurol 1994; 3 The non-Hodgkin’s lymphoma pathological the cervical region, extending throughout the 42:489–93. classification project: the National Cancer thoracic cord, and deviating to the left at the 3 Pujol J, Roig C, Capdevila A, et al. Motion of the Institute sponsored study of classifications of cerebellar tonsils in Chiari type I malformation non-Hodgkin’s lymphomas. Summary and level of the lumbar cord (figure). Many anal- studied by cine phase-contrast MRI. Neurology description of a working formulation for gesic, antidepressive, antiepileptic, and an- 1995;45:1746–53. clinical usage. Cancer 1982;49:2112–39. tiarrhythmic drugs had previously failed or 4 Williams B. The cystic spinal cord. J Neurol 4 Lutz JM, Coleman MP. Trends in primary cer- failed again in our hands, as did sympathetic Neurosurg Psychiatry 1995;58:649–54. ebral lymphoma. Br J Cancer 1994;70:716–8. 5 Milhorat TH, Johnson RW, Milhorat RH, 5 Miyoshi J, Kubonishi I, Yoshimoto S, Hikita T, blockade or transcutaneous electrostimula- Capocelli AL Jr, Pevsner PH. Clinicopatho- Dabasaki H, Taraka T, et al. Characteristics of a tion. Implantation of an epidural stimulator logical correlations in syringomyelia using axial brain lymphoma cell line derived from primary gave considerable relief, the intensity of the magnetic resonance imaging. Neurosurgery intracranial lymphoma. Cancer 1982;49:456–9. 1995;37:206–13. pain decreasing by more than half; this was 6 Milhorat TH, Kotzen RM, Mu HTM, Ca- sustained up to the last contact, nine months pocelli AL Jr, Milhorat RH. Dysesthetic pain in Attacks of pain in the leg from classic after implantation. patients with syringomyelia. Neurosurgery 1996;38:940–6. syringomyelia Leg pain with syringomyelia has so far been reported only in patients with a syrinx Neurologists should not be surprised if the confined to the lumbosacral cord, secondary Anti-GQ1b and anti-GT1a IgG anti- to trauma or tumour.12 In our patient bouts cause of a disorder is remote from its eVect, bodies in a patient with acute such as a parasagittal meningioma causing of pain in the leg were associated with classic syringomyelia, which starts at the level of the demyelinating polyradiculoneuropathy foot dragging, or a sacral ependymoma lead- without ophthalmoplegia ing to deafness as the first sign of siderosis of cervical cord and results from obstruction of the nervous system. Yet we were for some the CSF flow at the foramen magnum, most commonly by tonsillar ectopia.34We propose Anti-GQ1b IgG antibodies have been often time bewildered by the following problem. detected in the serum of patients with Miller A 67 year old woman consulted us in 1996 that the pain resulted from disturbed impulse transmission in the posterior grey matter at Fisher syndrome or Guillain-Barré syndrome for attacks of pain in the left leg that had with ophthalmoplegia. These antibodies may started in 1978 and had gradually increased the left side of the lumbar cord, the pain par-

participate in the development of ophthalmo- copyright. in severity and frequency up to three to four tially matching the area of sensory loss. It is not unusual for symptoms to correspond to plegia. Our patient with acute demyelinating attacks an hour, each lasting a few minutes polyradiculoneuropathy had no ophthalmo- and so severe that she had to stop anything paracentral cavitations only, the central part of the syrinx being clinically silent.5 Dysaes- plegia despite having anti-GQ1b and anti- she was doing to nurse her pain. It was sharp GT1a IgG antibodies in her serum. and stabbing in character and radiated from thetic pain from a paracentral syrinx is known to occur in the arm.6 Also in those cases the An 80 year old woman was admitted the gluteal region to the groin, and further because of weakness of her limbs. Ten days down to the lateral part of the upper and response to surgical treatment is unpredictable.6 Epidural stimulation was the before admission to our hospital, after a com- lower leg. Between attacks she was com- mon cold, she developed diYculty standing pletely free of pain. The stabs also woke her only measure that made our patient’s life again bearable. and paraesthesia in her lower legs. Within a up at night, six or seven times. In 1988 inves- few days, walking and prolonged sitting were tigations at another hospital had established nearly impossible and her arms became weak. the diagnosis of cervical syringomyelia, sec- We are grateful to Dr HE van der Aa ( Enschede) for referring the patient and to AL Liem (St Antonius On the day of admission, she developed dys- ondary to tonsillar ectopia (Chiari I malfor- hospital, Nieuwegein) for implantation of the phagia. There was no diplopia or ptosis at any mation); a year later a syringopleural drain epidural stimulation device. time. http://jnnp.bmj.com/ Her ocular and facial muscles were normal. She had diYculty in drinking water. Her limbs were weak (upper limbs MRC grade 3/5 and lower limbs 2 to 3/5). Deep reflexes were diminished or abolished. Pathological reflexes were not elicited. Superficial and deep sensation were abnormal below the knees. Stool culture was negative for Campy-

lobacter jejuni. The CSF contained 159 mg on September 24, 2021 by guest. Protected protein/dl and no cells. The right tibial motor nerve conduction velocity (MCV) was slow and the peroneal nerve did not respond. The median and ulnar nerves showed delayed distal latencies. Slow- ing of sensory nerve conduction velocity (SCV) was found only in the median nerve. F waves could not be elicited from the median and tibial nerves. A sural nerve biopsy on the 24th day showed loss of myelinated fibres without cell infiltration. Dysphagia disappeared on the 27th day. Strength in her upper limbs recovered to MRC grade 4/5 a week later. One month after admission, she could walk with a little help. The protein concentrations in her CSF were 82 and 57 mg/dl after a month and four months respectively. Three months later, the T1 weighted MRI at the level of the D10-D11 intervertebral disc. Hypointense lesion in the left median and tibial MCVs were still slow and dorsolateral region of the lumbar cord, corresponding to the posterior horn. could not be elicited in the peroneal nerve. Letters, Book reviews 411 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from

The distal and F wave latencies in both the Laboratory for Glyco Cell Biology, Frontier Research three men, with a mean age of 59 (range median and ulnar nerves were delayed. F Program, The Institute of Physical and Chemical 54–66). All had typical ITN which at some waves could not be elicited in the peroneal or Research (RIKEN), 2-1 Hirosawa, Wako 351-01, point could no longer be controlled by drugs tibial nerves. Median SCV did not improve. Japan at adequate dosage. In all other cases, the The patient was discharged with no disability Correspondence to: Dr Kouichi Mizoguchi. vessels were separated from the root by inter- in activities of daily life four months after posing Surgicel; the arachnoiditis was dis- admission. 1 Mizoguchi K, Hase A, Obi T, Matsuoka H, sected to free the root and, in one patient with The patient’s serum was tested at intervals Takatsu M, Nishimura Y, et al. Two species of slight venous compression partial (25%) for antiganglioside antibody activities by en- anti-ganglioside antibodies in a patient with a rhizotomy was also carried out. In several pharyngeal-cervical-brachial-variant of Guillain- 1 patients, “massage” of the trigeminal root was zyme linked immunosorbent assay (ELISA). Barré syndrome. J Neurol Neurosurg Psychiatry GM1a, GM2, GM3, GD1a, GD1b, GT1a, 1994;57:1121–3. performed. GT1b, and GQ1b were prepared from bovine 2 Hirabayashi Y, Nakao T, Matsumoto M. Im- All patients were relieved by surgery. 2 proved method for large-scale purification of Follow up disclosed the following recur- brain. The antigenic solution contained 20 brain gangliosides by Q-sepharose column pmol/50 µl of each ganglioside. Each patient’s chromatography. Immunochemical detection rences: two in group 1 (follow up 4 months-9 serum was tested in triplicate at 1:100 of C-series polysialogangliosides in adult bo- years), none in group 2 (follow up 2.3–5 vine brains. J Chromatography 1988;445:377– years), none in group 3 (follow up 1.1–5 dilution, and binding detected with horse 84. radish peroxidase conjugated goat antihuman 3 Chiba A, Kusunoki S, Obata H, Machinami R, years), two in group 4 (follow up 1–6 years), IgM or IgG antibody (Jackson Immunore- Kanazawa I. Serum anti-GQ1b IgG antibody is one in group 5 six years postoperatively (fol- search Laboratories, Inc, West Grove, PA, associated with ophthalmoplegia in Miller low up 6 months-8 years). Importantly, one Fisher syndrome and Guillain-Barré syndrome: of the group 1 recurrences was operated on USA) at 1:1000 dilution. On admission, the clinical and immunohistochemical studies. serum reacted with both GQ1b and GT1a at Neurology 1993;43:1911–7. and no vascular contact whatsoever could be a dilution of 1:3200. These two antibody 4 Yuki N. Acute paresis of extraocular muscles found (partial rhizotomy was elected). The associated with IgG anti-GQ1b antibody. Ann only group 5 recurrence could be controlled activities, expressed as optical densities, fell to Neurol 1996;39:668–72. 1/2 in parallel with her improvement, but they 5 Kimura T, Kira J, Kohtake N, Goto I, Yuki N. by drugs. Whereas this was seen in other could still be detected in her last blood sam- Acute relapsing sensory dominant polyneu- groups as well, all four group 5 patients ple (at 16 weeks). IgG antibodies against the ropathy associated with anti-GQ1b antibody showed transient slight to moderate hypaes- and autoimmune hepatitis. Clin Neurol 1994; thesia in two to three branches after surgery, other gangliosides were not detected at any 34:886–91. time, nor were IgM antibodies to any a hallmark of trauma. ganglioside detected. In 1961, Taarnhøj reported that simple To determine whether these two antibodies Can trauma alone to the trigeminal root manipulation of the trigeminal root by react independently with each ganglioside or relieve trigeminal neuralgia? The case running a nerve hook along the root obtained react with a common epitope sharing with against the microvascular compression 60% long term pain free results over a mean 4 GQ1b and GT1a, an absorption study was hypothesis of 6.5 years (longest follow up 10 years). performed using GQ1b or GT1a coated Gardner and Miklos also obtained 67% pain polystyrene beads as described previously.1 Idiopathic trigeminal neuralgia (ITN) is free results over 4.5 years by manipulating the increasingly regarded as being due to micro- trigeminal sensory root at the point of cross- The titre of anti-GQ1b IgG antibody de- 5 creased when preincubated with GT1a vascular compression of the trigeminal sen- ing the apex of the petrous bone, suggesting that manipulation not at the root entry zone coated polystyrene beads, and vice versa for sory root, either by an artery or a vein close to copyright. 1 the anti-GT1a IgG antibody. Based on these the brainstem. Yet vascular contacts are (as suggested by Jannetta), but peripherally at results, we hypothesised that these antibodies found in entirely asymptomatic cases, no vas- the petrous apex produces as good results as reacted with a common epitope sharing cular contacts are found in some asympto- microvascular decompression. As no other report considered the problem, the microvas- GQ1b and GT1a. matic patients, and, most importantly, ITN cular compression hypothesis for ITN gained Chiba et al3 found anti-GQ1b IgG antibod- suddenly switches oV, even for years, only to favour. Our data suggest that (1) trauma ies in patients with Miller Fisher syndrome and return later, in the face of continuing vascular 2 alone can ensure long term relief; (2) this also with Guillain-Barré syndrome with oph- compression. Despite this, microvascular relief is similar between patients showing thalmoplegia. They showed immunochemi- decompression produces immediate virtually microvascular compression and those with- cally that GQ1b was rich in the paranodal complete (98–100%) relief in 82% of the 3 out; it should be stressed that several patients regions of the human oculomotor, trochlear, cases and 64% after 10 years. Adams has of the microvascular compression group were and abducens nerves. These anti-GQ1b IgG suggested that, ITN being a hyperfunctional 4 disorder of the brainstem, microvascular “massaged” to ensure a control with the antibodies also reacted with GT1a. Yuki et al group without. found anti-GQ1b IgG antibodies in eight decompression “produces chronic trauma to The trigeminal nerve root is surrounded by http://jnnp.bmj.com/ patients with acute paresis of the extraocular a sensitive zone of the cranial nerve... by the many arteries. In 60% of the roots, the muscles but without ataxia. These results sug- dissection necessary and by the manipulation trigeminal vessels form arterial rings encir- gested that anti-GQ1b IgG antibodies had a required microvascular decompression pro- cling at least half of the root or its entry zone part in the development of ophthalmoplegia. duces suYcient trauma to achieve interfer- ence of normal functioning of that nerve”, in asymptomatic patients,6 justifying the We have also detected anti-GQ1b and anti- thus dampening the abnormal brainstem frequency of vascular contacts at large. GT1a IgG antibodies in six patients with activity responsible for ITN.2 Failure to Despite a plethora of vessels reported to Miller Fisher syndome and two with Guillain- achieve an initial result or early recurrence compress the trigeminal nerve in a recent Barré syndrome accompanied by ophthalmo- would imply insuYcient surgical trauma.2 We series,3 initial relief could not be achieved in plegia.We also found that these antibodies evaluated this hypothesis in our patients sub- 18% of the patients. Recently, a group on September 24, 2021 by guest. Protected reacted with a common epitope sharing GQ1b mitted to microvascular decompression. reported electrophysiological data supporting and GT1a (unpublished data). Kimura 5 et al Forty one out of 410 patients with ITN have the concept of trauma during microvascular have already reported a patient with acute had keyhole microvascular decompression in decompression, despite attempts to limit the relapsing sensory dominant polyneuropathy the posterior fossa from December 1986 to procedure to simply moving the vessel.7 The without ophthalmoplegia who had an anti- February 1996 at the neurosurgical pain trauma hypothesis would explain recurrences GQ1b IgG antibody which did not react with relief unit of the University of Turin. Twenty of successful microvascular decompression in GT1a. Further clarification of the relation six patients showed pronounced arterial or which no new compression is found (for between anti-GQ1b IgG antibody and the 8 arterovenous compression, three distally example, our case and see Yamaki et al )at development of ophthalmoplegia in Miller (group 1), three mild or disputable contacts re-exploration. Fisher syndrome or Guillain-Barré syndrome (group 2), two slight and three pronounced Adam’s contention is being appreciated in is required. venous compressions (group 3), five with the case of hemifacial spasm. Payner and KOUICHI MIZOGUCHI arachnoiditis, two with a sharp root kink, four Te w, 9 discussing their results with microvas- TSUYOSHI UCHIYAMA distally (group 4). In four cases (group 5), no cular decompression for this disorder, stated TOMOKAZU OBI anomaly whatsoever could be found, despite that “...perhaps there is truth that the early MASAHIRO SERIZAWA adequate magnification and careful explora- success in most patients results from minor YOSHIROU NISHIMURA tion; vessels were noted close to the root, but trauma... to support this theory, additional Department of Neurology, National Shizuoka no contact or groove could be seen. Thus the analysis is needed of the long term follow up Hospital, 24-1 Joto-cho, Shizuoka, 420, Japan root was gently “massaged” with a microdis- in patients without vascular compression FUMITOSHI IRIE sector; no other manoeuvre was attempted. and...treated by “manipulation” alone”. This YOSHIO HIRABAYASHI These four patients included one woman and is what has been done in this study. 412 Letters, Book reviews J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from

Microvascular decompression entails a risk of haemorrhage resulted in compression of the clinical description of this important phenom- death (although this is small) and other seri- superior face of the left cerebellar hemisphere enon was made by Pierre Marie. ous complications requiring surgery (much and caused a protrusion of the cerebellar FABIO SIMONETTI more often) in the face of a painful, but tonsils that “appeared to have engaged the PAOLA PERGAMI benign disorder. Perhaps, “trauma surgery” occipital foramen”. MAURO CERONI would be best to ensure equal results with a Pierre Marie drew attention to the patho- Neurological Institute, IRCCS C Mondino, University much lower complication rate. A minimally physiological research of Leonard Hill. “In of Pavia, via Palestro 3, Pavia, Italy invasive approach (endoscopy) could be his Hunterian Lectures in 1896, he showed ALAN H ROPPER studied in this regard. that the brain does not transmit the pressure St Elizabeth’s Medical Center, Division of Neurology, SERGIO CANAVERO on one point in all directions. Indeed, a clear 736 Cambridge St, Boston MA 02135, USA VINCENZO BONICALZI pressure diVerence is created between the ROBERTO VIVIANI PAOLO FERROLI main cranial cavity and the posterior fossa. Department of Psychiatry, University of Cambridge, Pain relief unit, Department of Neurosciences, Ospedale According to Hill, the pressure gap is due to: Addenbrooke’s Hospital, Level 4, Hill Road, Molinette, Turin, Italy (1) the viscosity of the cerebral substance; (2) Cambridge, UK Correspondence to: Dr S Canavero, Via Mon- the interposition of the falx cerebri and the temagno 46, 10132 Torino, Italy. tentorium cerebelli. This explains why a Correspondence to: Dr M Ceroni, Istituto Neuro- logico “Fondazione C Mondino” via Palestro 3, haemorrhage lesion exerts a localised com- 27100 Pavia, Italy. 1 Møller AR. The cranial nerve vascular compres- pression on a particular part of the cerebrum, sion syndrome. II. A review of pathophysiology. instead of creating a uniform pressure growth 1991; :24–30. Acta Neurochir (Wien) 113 on the whole cerebral mass, as some think. In 1 Lundberg N. Continuous recording and control 2 Adams CBT. Microvascular compression: an of ventricular fluid pressure in neurosurgical alternative view and hypothesis [review article]. the present circumstance, the compression is practice. 1989; :1–12. Acta Psychiatrica et Neurologica Scan- J Neurosurg 57 exerted on a cerebellar hemisphere. dinavica 1960;36(suppl 149):64–72. 3 Barker FG, Jannetta PJ, Bissonette DJ, Larkins 2 Meyer A. Herniation of the brain. MV, Jho HD. The long-term outcome of Furthermore, according to Leonard Hill Arch Neurol “the compression exerted by the haemor- Psychol 1920;4:387–400. microvascular decompression for trigeminal 3 Howell DA. Upper brain-stem compression neuralgia. N Engl J Med 1996;334:1077–83. rhaged cerebral hemisphere upon the supe- and foraminal impaction with intracranial 4 Tarrnhøj P. The place of decompression of the space-occupying lesions and brain swelling. posterior root in the treatment of trigeminal rior surface of the cerebellum can have very serious consequences. In fact, if the compres- Brain 1959;82:525–52. neuralgia [abstract]. J Neurol Neurosurg Psy- 4 Cushing H. 1961; :295–96. Tumours of the nervus acusticus and chiatry 24 sion is suYciently strong, the downward push syndrome of the cerebellopontine angle. 5 Gardner WJ, Miklos MV. Response of trigemi- on the cerebellum causes the engagement of Philadelphia: Saunders, 1917. nal neuralgia to “decompression” of sensory its inferior surface into the foramen magnum. 5 Collier J. The false localizing signs of intracra- root. Discussion of cause of trigeminal neural- nial tumours. l904; :490–508. gia. 1959; :1773–6. In this process the cerebellum takes the form Brain 27 JAMA 170 6 Cushing H. Strangulation of the nervi abdu- 6 Marinkovic SV, Gibo H. The blood supply of of two cones constituted by the cerebellar the trigeminal nerve root, with special refer- centes by lateral branches of the basilar artery in cases of brain tumour. 1910; :204– ence to the trigeminocerebellar artery. Neuro- tonsils. As a result the medulla oblongata is Brain 33 1995; :309–17. trapped within the foramen magnum, and if 35. surgery 37 7 Marie P. Sur la compression du Cervelet par les 7 Stechison MT, Møller A, Lovely TJ. Intraopera- the pressure is strong enough its vessels will tive mapping of the trigeminal nerve root: tech- foyers d’hemorrhagie cerebrale. Comples rendus nique and application in the surgical manage- be compressed to the point of failing to sup- des seances et memoires de la Societe de Biologie et (ler juillet) 1899:572. ment of facial pain. Neurosurgery 1996;38:76– ply the organ. Hence a severe bulbar ischemia de ses Filiales, 82. will ensue.”7 8 Marie P. De l’engagement des amygdales 8 Yamaki T, Hashi K, Niwa J, Tanabe S, cerebelleuses a l’interieur du trou occipital copyright. Pierre Marie concluded his communica- dans les cas ou la pression intracranienne se Nakagawa T, Nakamura T, et al. Results of reintervention for failed microvascular decom- tion by considering the possibly severe conse- troube augmentee. Revue Neurologique (Paris) pression. 1992; :1–7. quences of cerebellar tonsillar penetration 1900;8:252–3. Acta Neurochir (Wien) 115 9 Alquier LPM. Deux cas d’heterotipie du cerve- 9 Payner TP, Tew JM Jr. Recurrence of hemifacial into the occipital foramen and the resulting spasm after microvascular decompression. let dans le canal rachidien. Revue Neurologique 1905; :1117–8. Neurosurgery 1996;38:686–91. bulbar hypoperfusion, exactly devising the (Paris) 13 mechanism of cerebellar herniation. In the 10 Fisher CM. Brain herniation: a revision of clas- sical concepts. 1995; :83–91. next year, Pierre Marie reported the patho- Can JNeurol Sci 22 About the original description of logical findings of another two cases of raised cerebellar tonsil herniation by Pierre intracranial pressure.8 In the first case with a Blepharospasm induced by flunarizine Marie thalamic haemorrhage the rise in intracranial pressure caused the caudal shift of a cerebel- Flunarizine is a calcium channel antagonist Transfalcial and transtentorial herniation and lar tonsil, that consequently “engaged into that has been widely prescribed for vertigo, the engagement of the cerebellar tonsils into the occipital foramen”. The second case was cerebral or peripheral vascular diseases, the foramen magnum are well recognised of increased intracranial pressure of unknown migraine, and epilepsy.12At doses of 10-40 http://jnnp.bmj.com/ consequences of increased intracranial pres- origin, disclosed by pronounced hydrocepha- mg/day, it can produce side eVects such as sure. They were discovered through both lus. “Both cerebellar tonsils had shifted into parkinsonism or abnormal involuntary move- experimental findings carried out in the 19th the occipital foramen such as to form a sort of ments, especially in elderly people.12A case of century,1 and pathological and clinical expe- cone enclosing the bulbus for more than half blepharospasm in a 67 year old woman who riences reported in the first decades of this of its circumference.” In his conclusions, had been taking 20 mg/day flunarizine for 18 century.2 Harvey Cushing (1869–1939) is Pierre Marie suggested that the compression months has been reported.2 However, the usually acknowledged as the first clinician of the medulla could have contributed to the cause of the disorder in this instance may be who, in 1902, correlated the clinical picture fatal outcome. questionable as this patient had also been of neurological disturbances and cardiorespi- A few years later, in 1905, Louis Pierre treated with cinnarizine and her dystonic on September 24, 2021 by guest. Protected ratory failure with the herniation of the Marie Alquier (1872–1956) described two movements did not disappear 13 months cerebellar tonsils into the foramen magnum.3 further cases of cerebellar tonsils herniation after the discontinuation of both drugs.2 We However, when in his book on pontocerebel- into the occipital foramen.9 In Alquier’s arti- have seen a 30 year old woman who was lar angle tumours Cushing made use of the cle the discussion of Jean Athanase Sicard treated with 10 mg/day flunarizine for notion of “cerebellar pressure cone”,4 he was (1872–1929) and Pierre Marie on the topic is migraine prophylaxis. After two months of employing a term first introduced into the reported. Mentioning his personal experience treatment she developed a progressive English language by Collier,5 as Cushing in similar cases, Pierre Marie also made the blepharospasm which eventually prevented himself acknowledged in an earlier article.6 somewhat surprising suggestion that Alqui- her from reading or watching television. Here we report on the observations of er’s pathological findings might be attributed Three weeks after the appearance of symp- Pierre Marie (1853–1940) that bear on the to a postmortem process. We could find no toms, flunarizine was withdrawn, and the same issue and antedate those of both Cush- further contribution by Pierre Marie on this patient made a gradual and complete recov- ing and Collier. On l July 1899, during a ses- topic in his subsequent scientific production. ery over the next month. sion of the Societé de Biologie, Pierre Marie7 Recently, Fisher10 has pointed out that cer- Dopaminergic, cholinergic, serotoninergic, reported on two cases of cerebral haemor- ebellar herniation is not necessarily a terminal or other poorly understood mechanisms rhage that resulted in secondary compression event, except, in cases in which cerebellar her- might be implicated in the pathogenesis of of the cerebellum. In the first case, a haemor- niation occurs in posterior fossa infarcts, blepharospasm.3 Flunarizine has been re- rhage of the external segment of the lenticu- acute subdural haematomas, or during a lum- ported to have antihistaminic, antiserotonin- lar nucleus flattened the superior face of the bar puncture. In such cases, acute herniation ergic, and antidopaminergic activities.2 This left cerebellar lobe and shifted the vermis to is justifiably considered among the determi- interference with dopaminergic transmission the right. In the second case, a thalamic nant factors of clinical outcome. The first seems to be both complex and particularly Letters, Book reviews 413 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from relevant. On the one hand, flunarizine blocks with the angiogenesis12 and also a possible tenascin as well as a grade IV tumour dopamine receptors and might have a toxic target for therapy. To verify these opinions we evaluated as T4. eVect on dopaminergic neurons.4 On the have performed an immunohistochemical In conclusion, we have shown that tenascin other hand, its calcium channel antagonism analysis of 10 astrocytic tumours of the does not correlate with the indices of leads to inhibition of dopamine neuro- cerebral hemispheres. The series of patients malignancy we have studied—namely, grad- transmission.4 In addition, the antihistaminic comprised six men and four women, ranging ing, PCNA labelling index, and size of the activity of flunarizine may also have some in age from 43 to 72 years; seven underwent tumour. The presence of tenascin in the importance. The blepharospasm that occa- gross total resection and three subtotal resec- extracellular matrix could only be a signal of sionally follows the use of decongestants has tion. The study focused on the following progression of astrocytic tumours. This could been explained by the antihistaminic compo- molecules of the extracellular matrix: te- explain its presence in the gemistocytic astro- nent of these drugs.5 Whatever the mecha- nascin, laminin, fibronectin, and type IV col- cytoma, which is well known as a tumour with nisms involved, the early development of lagen. The results were evaluated in relation a high probability of progression. blepharospasm in a young adult on a low dose to the following indices: grading according to Furthermore, it is well known in oncology of flunarizine would suggest that individual the St Anne/Mayo System,3 proliferating cell that the size of the tumour must correlate susceptibility played a part in its emergence. nuclear antigen labelling index,4 dimensions with neoangiogenesis.6 Our hypothesis is that The present case would favour the inclusion of the tumour evaluated radiologically (CT if the expression of tenascin does not of flunarizine among the causes of isolated and MRI) and expressed according to the correlate with the dimension of the tumour it blepharospasm. criteria of the manual for staging of cancer by cannot really correlate with the angiogenesis. 5 A KOUKOULIS means of the parameter “T”. J S HERRERO Primary monoclonal antibodies were pur- This work was supported by the contribution of the J GÓMEZ-ALONSO chased from Dako and staining was per- Department of experimental and clinical medicine Neurology Department, Hospital Xeral, Pizarro 22 formed by the labelled streptavidin biotin of the University of Reggio Calabria. 36204 Vigo, Spain staining method on 10% formalin fixed and G DONATO Correspondence to: Dr A Koukoulis. paraYn embedded tissue. A LAVANO The tumours were grade II in two cases G VOLPENTESTA D CHIRCHIGLIA 1 Chouza C, Scaramelli A, Caamaño JL, De (one gemistocytic), grade III in three cases, C D SIGNORELLI Medina O, Aljanati R, Romero S. Parkinson- and grade IV in five cases. Tenascin was Department of Neurosurgery of the University of ism, tardive dyskinesia, akathisia, and depres- present in the extracellular matrix in all grade sion induced by flunarizine. Lancet Reggio Calabria, School of Medicine (Catanzaro), 1986;i:1303–4. IV astrocytomas and in the gemistocytic Italy 2 Micheli FE, Fernández Pardal MM, Giannaula astrocytoma. In two grade III astrocytomas L TUCCI R, Gatto M, Casas Parera I, Paradiso G, et al. and in all grade IV astrocytomas the base- Movement disorders and depression due to Department of Pathology, General Hospital flunarizine and cinnarizine. Mov Disord 1989;4: ment membranes of the vessels with or with- “A Pugliese” (Catanzaro), Italy 139–46. out endothelial proliferation showed a posi- Correspondence to: Dr G Donato, Department of 3 Jankovic J, Ford J. Blepharospasm and orofacial- tive immunohistochemical staining for Neurosurgery, Policlinico “Mater Domini”, Via T cervical dystonia. Clinical and pharmacological tenascin (figure).Tenascin and fibronectin Campanella, 88100 Catanzaro, Italy. findings in 100 patients. Ann Neurol 1983;13: 402–11. were detected in some neoplastic cells of 4 Mena MA, García de Yébenes MJ, Tabernero grade IV tumours and also in the gemisto- 1 Higuchi M, Ohnishi T, Arita N, Hiraga S, Hay- C, Casarejos MJ, Pardo B, García de Yébenes cytes. Laminin, fibronectin, and collagen type akawa T. Expression of tenascin in human glio- J. EVects of calcium antagonists on the copyright. IV were found around the vessels of tumours mas: its relation to histological malignancy, dopamine system. Clin Neuropharmacol 1995; tumor dediVerentiation and angiogenesis. Acta 18:410–26. of all grades.The PCNA labelling index was Neuropathol 1993;85:481–7. 5 Powers JM. Decongestant-induced blepharos- <1% in tumours of grade II and grade III. In 2 Zagzag D, Friedlander DR, Miller DC, Dosik J, pasm and orofacial dystonia. JAMA 1982;247: Cangiarella J, Kostianovsky M, et al. Tenascin 3244–5. grade IV tumours the areas of highest PCNA staining did not correspond to the greater expression in astrocytomas correlates with ang- iogenesis. Cancer Res 1995;55:907–14. expression of tenascin on serial sections. In 3 Daumas-Duport C, Scheitauer B, O’Fallon J, Expression of tenascin in astrocytic some areas with strong staining for tenascin Kelly P. Grading of astrocytomas. A simple and tumours: too much ado about nothing? the PCNA labelling index was <5%, whereas reproducible method. Cancer 1988;62:2152– 65. the total percentage in grade IV tumours 4 Louis DN, Edgerton S, Thor AD, Hedley- The stroma of astrocytic tumours has been ranged from 5% to 18%. Whyte ET. Proliferating cell nuclear antigen investigated in the past years by various Evaluation of the parameter “T” failed to and Ki-67 immunohistochemistry in brain authors. Among the proteins of the extracel- provide a correlation between the size of the tumors: a comparative study. Acta Neuropathol 1991;81:675–9. lular matrix tenascin is considered a very tumour and the presence of the molecules of 5 American Joint Committee on Cancer. Manual important molecule because of presumed the extracellular matrix. For instance, a grade for staging of cancer. 4th ed. Philadelphia: http://jnnp.bmj.com/ links with the malignancy of the tumours and IV tumour evaluated as T1 expressed the Lippincot, 1992;247–50. 6 Folkman J. The role of angiogenesis in tumor growth. Cancer Biol 1992;3:65–71.

Multiple sclerosis associated with duplicated CMT1A: a report of two cases

The concomitant involvement of both the on September 24, 2021 by guest. Protected peripheral and central nervous system myelin is rare and may occur in the course of inher- ited lysosomal storage diseases. In inflamma- tory autoimmune diseases of the peripheral nervous system or CNS, a mild involvement of central or peripheral myelin has sometimes been reported.12 In such conditions, a single pathogenetic mechanism has been tentatively considered as responsible for the nervous tis- sue damage and the association of peripheral nervous system and CNS demyelinating dis- orders due to diVerent pathogenetic mecha- nisms has never been reported. We describe two patients with definite multiple sclerosis and hereditary peripheral neuropathy of Charcot-Marie-Tooth type 1A (CMT1A). Patient 1, a 38 year old woman, was admit- Glioblastoma. Immunohistochemical staining for tenascin is in the basement membrane zone of ted to hospital because of episodes of gait tumour vessels and also in the extracellular matrix (originally ×125). disturbances and optic neuritis. Neurological 414 Letters, Book reviews J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from examination showed ataxia, lower limb weak- polyradiculoneuropathy (CIDP) as the con- for the occurrence of autoimmune disorders ness, bilateral Babinski’s sign, increased ten- sequence of a peripheral nervous system targeted to the CNS myelin. don reflexes, mild sensory loss in all four limbs, invasion by the same pathological process We suggest that patients with multiple impaired bladder function, and bilateral pes aVecting the CNS. Our patients did not fulfill sclerosis must be carefully evaluated for the cavus. Her CSF showed an IgG index of 0.89 laboratory criteria for CIDP. In addition, the presence of peripheral nervous system in- and IgG oligoclonal bands. Electrophysiology anamnestic presence of foot abnormalities in volvement. In such circumstances, neuro- disclosed features of CNS and peripheral family members suggested inherited neu- physiological, neuropathological, and genetic nervous system demyelination (table). ropathy. Finally, the detection of characteris- analyses may greatly contribute towards a Patient 2, a 30 year old woman, had had tic genetic alterations in chromosome 17 correct diagnosis. recurrent episodes of hemiparesis and para- confirmed the diagnosis of CMT1A. This work was supported by grant 750 95 from Tel- paresis, optic neuritis, and facial palsy since Aspects of CNS involvement have been ethon Italy. the age of 22. When admitted to our depart- reported in CMT1 and also in hereditary 4 EMMA FRASSON ment, she had spastic paraplegia, absent neuropathy with liability to pressure palsy, ALBERTO POLO ankle tendon reflexes, bilateral Babinski’s the last being caused by a reciprocal deletion ALFONSINA DI SUMMA sign, distal loss of vibration in the legs, of the region duplicated in CMT1A; these GIANNI FABRIZI impaired visual acuity, internuclear opthal- changes have been tentatively attributed to an FEDERICA TAIOLI moplegia, and ataxic speech. Bilateral pes increased or decreased expression of periph- ANTONIO FIASCHI cavus was found in the patient as well as in eral myelin protein (PMP) 22 within the NICOLÒ RIZZUTO several members of her family. Her CSF CNS. However, this is the first report GIUSEPPE MORETTO showed an IgG index of 0.98 and IgG oligo- describing an association of multiple sclerosis Sezione di Neurologia Clinica, Dipartimento di clonal bands. Brain MRI showed di use foci and CMT1A. CMT1A encompasses most of Scienze Neurologiche e della Visione, Universita’ di V Verona,Italy of demyelination in the white matter of the the cases of CMT and is associated with a cerebral hemispheres and in the spinal cord. duplication in chromosome 17 p11.2-12 Correspondence to: Dr Giuseppe Moretto, Sezione di Neurologia Clinica, Policlinico Borgo Roma, Neurophysiological studies disclosed aspects where the PMP22 gene is located. PMP22 is 37134 Verona, Italy. of CNS and peripheral nervous system mainly expressed in the peripheral nervous demyelination (table). system, but it shares similarities with other 1 Thomas PK, Walker RWH, Rudge P, Morgan- In both patients sural nerve biopsy showed proteins of the CNS such as the proteolipid Hughes JA, King RHM, Jacobs JM, et al. Chronic demyelinating peripheral neuropathy loss of myelinated fibres and aspects of protein. In duplicated CMT1A, myelin devel- associated with multifocal central nervous sys- demyelination and remyelination with onion opment is normal, but an overexpression of tem demyelination. Brain 1987;110:53-76. bulb formation. PMP22 may aVect the maintenance of the 2 Schoene WC, Carpenter S, Behan PO, Ge- Genetic molecular analysis was performed peripheral nervous system myelin, which schwind N.“Onion bulb” formations in the 5 central and peripheral nervous system in associ- by CHEF-DRIII pulsed fields gel electro- undergoes progressive destruction. ation with multiple sclerosis and hypertrophic phoresis of the CMT1A Sac II junction The present finding raises the question polyneuropathy. Brain 1977;100:755-73. fragment.3 The detection of the novel junc- whether the concomitant presence of 3 Lorenzetti D, Pareyson D, Sghirlanzoni A, Roa BB, Abbas NE, Pandolfo M, et al.A1.5Mb tion fragment of 500 kb in both cases CMT1A and multiple sclerosis represents a deletion in 17p11.2-p12 is frequently observed indicated the presence of duplication. chance association or whether the genetic in Italian families with hereditary neuropathy Both patients had clinically definite multi- defect responsible for the peripheral neu- with liability to pressure palsies. Am J Hum ple sclerosis; in addition, the neurophysiologi- ropathy can play a part in triggering the Genet 1995;56:91-8. 4 Amato AA, Barohon RJ. Hereditary neuropathy cal, neuropathological, and genetic analysis autoimmune disorder of CNS myelin. We with liability to pressure palsies: association copyright. investigations disclosed a demyelinating and speculate that the PMP22 overexpression with central nervous system demyelination. remyelinating neuropathy of CMT1A. may also involve its antigenic properties, thus Muscle Nerve 1996;19:770-3. 5 Suter U, Welcher AA, Snipes GJ. Progress in the The involvement of the peripheral nervous inducing modifications of self tolerance. In molecular understanding of hereditary periph- system in the course of multiple sclerosis has this context, the partial homology among eral neuropathies reveals new insights into the been previously reported.12The authors sug- peripheral nervous system and CNS proteins, biology of the peripheral nervous system. TINS gested the diagnosis of chronic inflammatory such as the proteolipid protein, could account 1993;16:50-6.

Table 1 Neurophysiological studies Distal myasthenia gravis and sensory neuronopathy with anti-50 kDa Patient 1 Patient 2 Normal antibody mimicking sensory-motor MNC Ampl(mV) 0.5 12.0 neuropathy Median DL (ms) 10.0 13.0

CV (m/s) 18.6 24.7 Bilateral foot drop, paraesthesiae, and absent http://jnnp.bmj.com/ Ampl(mV) − 8.0 Ulnar DL (ms) − 9.0 tendon reflexes in the lower limbs are, for the CV (m/s) − 20.1 clinical neurologist, the hallmarks of a Ampl(mV) 1.0 NE duration dependent sensory-motor neu- Peroneal DL (ms) 8.7 NE ropathy. We report a patient in which this CV (m/s) 18.6 NE clinical picture was sustained by the combi- SNC Ampl (µV) 4.0 NE nation of an atypical distal presentation of Sural DL (ms) 5.8 NE CV (m/s) 26.0 NE myasthenia gravis with a probable immuno- SSEPS: mediated sensory neuronopathy.

Median NE NE A 69 year old woman presented with a on September 24, 2021 by guest. Protected Tibial NE NE three month history of progressive walking VEPs: diYculties and paraesthesiae in the lower Right Lat (ms) 151.0 149.0 P100 <118.0 limbs. Examination showed bilateral foot Ampl (µV) 14.7 6.4 >7.0 drop with pronounced weakness of the Left Lat (ms) 105.0 150.0 Ampl (µV) 17.9 5.4 tibioperoneal muscles (MRC= 2) and poste- BAERs: rior leg muscles (MRC= 3), slight weakness Right I (ms) 1.66 1.66 in arm abduction (MRC=4+), tactile and III (ms) 3.80 4.07 pain distal sensory loss, and absent tendon V (ms) 5.56 NE I <1.72 jerks in the lower limbs. There were no Left I (ms) 1.54 1.59 I–III <2.37 oculobulbar symptoms and signs nor ataxia. III (ms) 3.68 3.64 I–V <4.30 V (ms) 5.48 NE Motor conduction velocities and com- MEPs: pound muscle action potential (CMAP) Thenar PCT (ms) 26.0 28.9 <14.5 amplitudes were normal (ulnar= 57 m/s, 9.7 CCT (ms) 15.0 32.8 <10.0 mV; peroneal= 44 m/s, 3.9 mV). Sensory Tibial ant PCT (ms) 28.0 NE <15.4 conduction velocities were slowed with re- CCT (ms) 32.0 NE <18.0 duced amplitude sensory nerve potentials MNC=Motor nerve conduction; SNC=sensory nerve conduction; Lat=latency; Ampl=amplitude; (ulnar=44 m/s, 5 µV; sural= 30.6 m/s, 1.8 DL=distal latency; CV=conduction velocity; BAERs=waves I-III-V; VEPs=P100; MEPs=hand and leg µV). H reflexes were absent with normal muscles; PCT=peripheral conduction time; CCT=central conduction time; −=not performed; NE=not latency F responses. Tibialis anterior muscle evoked. EMG did not show spontaneous activity and Letters, Book reviews 415 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from recruitment was full but during prolonged bar signs.2 Peroneal nerve repetitive stimula- maximal voluntary activation there was a tion, as recently described by Oh et al,3 was pronounced reduction of the interferential crucial to the confirmation of myasthenia pattern amplitude. Quantitative motor unit gravis in this patient. analysis showed a 20% reduced mean dura- Clinical, electrophysiological, and histo- tion with 4% of polyphasics. Repetitive logical findings also showed an axonal stimulation at 3 Hz documented in the ulnar sensory neuropathy. Although there are no nerve-abductor digiti minimi system a 10% electrophysiological or morphological ways decrement whereas in the peroneal nerve- to distinguish between an axonal sensory extensor digitorum brevis system the decre- neuropathy and a sensory neuronopathy, the ment was 33%. Amplitude CMAPs in the reactivity of our patient’s IgG against small abductor digiti minimi after 15 seconds of size dorsal root ganglia (figure) suggests a maximal voluntary activation increased by primary, probably immunomediated, involve- 29%. A tensilon test, assessing strength in the ment of sensory neurons. The patient’s serum tibioperoneal muscles, was strongly positive. strongly immunostained, in a fine granular Sural nerve biopsy showed a loss of myeli- pattern, the cytoplasm of Purkinje cells and in nated fibres. Anti-AChR antibody titre was western immunoblotting the IgG reacted 3.3 nM (normal value<0.8). Voltage operated with a 50 kDa protein band present in whole calcium channel antibodies were negative. cerebellum and dorsal root ganglia homoge- Antibodies (IgG and IgM) against ganglio- nates (figure). These immunostaining and sides (GM1, GD1a, GD1b, GM2) , SGPG, immunoblot findings are clearly diVerent and sulphatides were negative. Chest CT from the features required for the identifica- excluded a thymoma or a lung cancer. A tion of anti-Yo and anti-Hu antineuronal 45 screening for breast, ovarian, and other antibodies. gynaecological malignancies was negative. In conclusion this case is unique for several Tumorous markers were negative. Foot drop reasons: was greatly improved with pyridostigmine (1) Clinical presentation pointed to a bromide and prednisone (75 and 25 mg every sensory-motor neuropathy but the foot drop other day) and after three months the patient was sustained by an atypical, distal presenta- did not complain of paraesthesiae and could tion of myasthenia gravis. walk on her toes and stand on her heels. (2) Peroneal nerve repetitive stimulation By indirect immunofluorescence,1 the pa- (not usually performed in EMG laboratories) tient’s IgG strongly reacted with the cyto- played an important part in confirming plasm of rat small size dorsal root ganglia myasthenia gravis. neurons up to a dilution of 1:1280, whereas it (3) Myasthenia gravis has been reported to did not react to large size dorsal root ganglia be associated with other autoimmune disor- neurons (figure). With an indirect immu- ders but never to a sensory neuronopathy noperoxidase technique,1 using sections of rat with antibodies reacting with dorsal root gan- copyright. cerebellum, the patient’s serum strongly glia neurons and Purkinje cells. immunostained the cytoplasm of Purkinje (4) 50 kDa antineuronal antibodies react- cells in a fine granular pattern up to a dilution ing with small size dorsal root ganglia neurons and in a fine granular pattern with of 1:2560. The patient’ serum did not react the cytoplasm of Purkinje cells have never with neurons of the molecular layer and Golgi been described previously. neurons. To determine whether the binding to Purkinje cells and dorsal root ganglia neurons The financial support of Telethon Italy to AU (project 520) and RN (project 613) is gratefully was due to the same antibody, the patient’s acknowledged. serum was adsorbed either with whole cer- A UNCINI ebellum homogenate or with dorsal root gan- G DI GUGLIELMO glia homogenate. The pretreatment with each A DI MUZIO of the two homogenates removed the tissue M REPACI binding activity, whereas liver homogenate A LUGARESI was without eVect. In the western immunob- Center for Neuromuscular Diseases of University of http://jnnp.bmj.com/ lot of whole human cerebellum homogenate, Chieti, Italy the IgG from our patient reacted with a 50 G M FORNO kDa protein band at dilutions up to 1:8000 R NEMNI (figure). Using whole dorsal root ganglia Department of Neurology, IRCCS H, San RaVaele, homogenate, the IgG from our patient reacted Milan, Italy with a 50 kDa protein band at dilutions up to Correspondence to: Dr Antonio Uncini, Clinica 1:1000. The pretreatment of serum either Top:binding of patient’s serum at a dilution of Neurologica, Ospedale Clinicizzato “SS Annun- with whole cerebellum homogenate or with 1:1280 to an unfixed frozen section of rat dorsal ziata”, 1-66013 Cheiti, Italy. whole dorsal root ganglia homogenate re- root ganglia by immunofluorescence microscopy. on September 24, 2021 by guest. Protected The patient’s IgG intensely immunostains the 1 Nemni R, Camerlingo M, Fazio R, Casto L, moved their blot binding activity, whereas Quattrini A, Mamoli D, et al. Serum antibodies liver homogenate was without eVect. cytoplasm of small size dorsal root ganglia neurons (arrows) but not with large size dorsal to Purkinje cells and dorsal root ganglia Clinical presentation in this patient root ganglia neurons (arrowhead) neurons in sensory neuronopathy without pointed to a sensory-motor neuropathy. Neu- × malignancy. Ann Neurol 1993;34:848–54. (originally 170). Middle: control serum does 2 Penn AS, Rowland LP. Myasthenia gravis. In: rophysiological studies documented an ax- not bind and stain the cytoplasm of rat dorsal LP Rowland, ed. Merrit’s textbook of neurology. onal sensory neuropathy but normal motor root ganglia(originally×170). Lower: lane 1: 7th ed. Philadelphia: Lea and Febiger, 1984: conduction. Normal CMAP amplitudes and immunoblot of human whole cerebellum 561–7. the borderline reduced mean duration value homogenate shows that at a serum dilution of 3 Oh SJ, Head T, Fesenmeier J, Claussen G. Pero- 1:8000 the patient’s IgG (lane 1) binds to a 50 neal nerve repetitive stimulation test: its value of motor unit potentials in tibialis anterior in diagnosis of myasthenia gravis and Lambert- muscle indicated that the foot drop did not kDa protein. Lane 2: positive control with Eaton myasthenic syndrome. Muscle Nerve anti-Hu antibodies binding to a 40 kDa protein. have a neurogenic origin. Repetitive stimula- 1995;18:867–73. Lane 3: negative control. Lane A: whole 4 Lennon VA: The case for a descriptive generic tion showed an unequivocal decremental cerebellum homogenate; lane B: molecular weight nomenclature: clarification of immunostaining response in the peroneal nerve (whereas the standard. Lanes 1–3, peroxidase conjugated criteria for PCA-1, ANNA-1, and ANNA-2 ulnar nerve was still in the normal range) assay. Lanes A and B, amido black staining. autoantibodies. Neurology 1994;44;2412–5. 5 Moll JWB, Antoine JC, Brashear MD, Dellattre indicating a defect in neuromuscular trans- J, Drlicek M, Dropcho EJ, et al. Guidelines on mission, more pronounced in leg muscles. drome. Myasthenia gravis was confirmed by the detection of paraneoplastic anti-neuronal- The normal CMAP amplitudes, the absence the raised titre of serum anti-AchR antibodies specific antibodies: report from the workshop to of incremental response, and the negativity of and the positive tensilon test. In myasthenia the fourth meeting of the International Society of Neuro-Immunology on paraneoplastic neurological voltage operated calcium channel antibodies gravis distal limb muscles are reported to be disease. 22–23 October 1994. Rotterdam, The ruled out a Lambert-Eaton myasthenic syn- almost never aVected in absence of oculobul- Netherlands. Neurology 1995;45:1937–41. 416 Letters, Book reviews J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.408 on 1 September 1997. Downloaded from

disease, particularly when that book weighs in walking with particular reference to the at less than 21lbs. This volume, however, goes vestibular system. This forms an essential BOOK REVIEWS a long way in achieving these admirable goals. basis for the rest of the book but is somewhat The volume is dedicated to Tom Sears who intimidating to the naive reader who may fail has recently retired from the Chair of the to get beyond discussions—for example, on Sobell Department of Neurophysiology, at the role of strategies or synergies in the con- Fronto-Temporal Lobar Degeneration: the Institute of Neurology in London. The trol of posture in response to balance distur- Fronto-Temporal Dementia, Pro- editors have gathered together an impressive bances. This would, therefore, prevent the gressive Aphasia, Semantic Dementia. list of contributors, and it is a tribute to Tom reader from entering the excellent section on Edited by: J S SNOWDEN, DAVID NEARY, AND D Sears that most of the authors acknowledge clinical disorders of balance and gait, and the M MANN. (Pp 227; £55.00). Published by the influence of Professor Sears and his assessment of such patients, a section that will Churchill Livingstone, Edinburgh 1996. coworkers in their chapters. There are over 40 appeal to most general neurologists. In this chapters, and most are only a few pages long. section of the book we are entertained by ISBN 0443047650. When trying to distill essential contributions some excellent chapters especially with re- made in any one field, there is inevitable vari- spect to the diverse and sometimes devastat- The three editors of this book have played a ation in the extent to which this is achieved ing symptoms and signs of vestibular disor- central part in the renaissance of interest in and in the readability between chapters. ders and the range of diVerent gait disorders the clinical, neuropsychological, and neu- The book is split into four sections: the first that can now be distinguished. Such disor- ropathological aspects of non-Alzheimer de- deals with physiology and pathophysiology of ders include the well recognised isolated gait mentias. This book is based on their truly nerve fibres, the second with pain, the third ignition failure as well as less widely known remarkable experience of some 200 patients with the control of nervous system output, states such as those gathered under the rubric with lobar atrophy studied over the past dec- and the fourth with development, survival, of subcortical disequilibrium states (includ- ade, 40 of whom have reached postmortem. regeneration, and death. There are concise ing thalamic astasia). In addition, there are It represents, therefore, an unequalled source contributions from Ritchie and Waxman on detailed discussions on the cautious gait and of information and is essential reading for all ion channels and the molecular anatomy of psychogenic disorders of gait and balance— those working in the area. the node of Ranvier which introduce the first cases of which abound in every neurological After a historical introduction, the initial section. Further chapters consider normal clinic. The classification and clinical features chapters are dedicated to the three princinpal central and peripheral nerve conduction of diVerent disorders of gait and balance are syndromes under consideration: frontotem- before dealing with disease. Throughout the complemented by chapters on the analysis poral dementia, progressive aphasia, and book the authors attempt to direct their con- and investigation of such patients from an semantic dementia. Each section integrates tributions of assessing why and how disease orthopaedic, neurological, and neuro- clinical neurology with neuropsychology, occurs. Newsom-Davis provides a chapter on otological point of view. This serves not only radiology, and pathology. There are also very autoimmunity at the neuromuscular junc- to highlight a strength of this book—namely, useful chapters which deal with diVerential tion, Feasby on the pathophysiology of human the multidisciplinary approach, but also high- diagnosis and the relation of lobar atrophy to demyelinating neuropathies, and McDonald lights the shortcomings of most neurological motor neuron disease. The final chapters are on the mechanisms of relapse and remission practices, which have limited access to special- more theoretically oriented and cover the role in multiple sclerosis. There is a well written ist neuro-otological units. In most centres the of the frontal lobes in behaviour and aspects chapter by Smith on conduction properties of patients are reviewed by non-specialist neu- of semantic memory. Besides the integrated central demyelinated axons and the genera- rologists and ear, nose, and throat surgeons copyright. approach and the highly readable style, the tion of symptoms in demyelinating disease. and then referred on to physiotherapists for other strength of the book is the liberal use of Pain is dealt with in the second section, and treatment, as pharmacological treatments are clinical vignettes and useful summaries at the this includes a readable chapter on myofacial generally not helpful. This aspect of the man- end of each chapter. The quality of illustra- pain syndromes by Westguard, as well as agement of patients with gait or balance tions is very high but more MRI images Shen’s attempt to assess the neurophysiologi- disorders is discussed in the three chapters would perhaps have been desirable. cal basis of pain relief by acupuncture. forming section four of this book, in which the Some readers naive to the field may emerge Part III deals with the control of central discussion concentrates on the psychological confused by the current terminologies, which nervous system output, and obviously con- and physical approach to treatment. cross levels of analysis: the newly adopted tains the widest range of topics. I would single The book closes with a rather repetitive term, frontotemporal dementia (which has out the chapters by Prochazka, Gorassini, and section on the specific problems of gait disor- replaced dementia of frontal type), has obvi- Taylor on the cerebellum and proprioceptive ders and falls in elderly people—an important ous neuroanatomical connotations, whereas control of movement, together with JeVerys’ and often neglected area of medicine which semantic dementia and progressive aphasia chapter on cortical circuit synchronisation will no doubt become more of an issue as the http://jnnp.bmj.com/ are syndrome terms which do not imply any and seizures. There are also several contribu- elderly population continues to grow. These direct anatomy or pathology. The relation tions relating to respiration. The final section chapters I found the most disappointing as between frontotemporal dementia and se- considers development, survival, regenera- they tended to be too wordy with little detail mantic dementia is perhaps one of the more tion, and death. This is the least inspiring part given to summary points—for example, in perplexing aspects of the current of the book, which is disappointing as this is chapter 20 there is an eight page table on all classification. Personally I would prefer use of currently the most exciting area of neuro- the studies that have analysed the eVects of the older term for a dementia of frontal type. science. medications on the risk of falls! The fact that neurodegenerative diseases Overall the editors have succeeded in con- Overall this book sets out to define and can produce very circumscribed cognitive densing a huge amount of information in a explore a much neglected area of neuro- deficits has been one of the most surprising readable and educative fashion. This book science and clinical neurology and goes a long on September 24, 2021 by guest. Protected and fascinating discoveries in recent years. will appeal to all those interested in clinical way to achieving this aim. The problem with This book admirably illustrates the value of neurology, both in training and practice, as a book such as this, however, is in trying to careful analysis of such cases, both for the well as those neuroscientists who seek to combine detailed technical accounts and understanding of the dementias and of broaden their own field of research. models for the specialist while holding the normal cognitive processes. I can wholeheart- interest of the neurologist. Ultimately the JOHN ZAJICEK edly recommend it. book has chapters of great value to the JOHN HODGES non-specialist neurologist, but these have to Clinical Disorders of Balance, Posture be looked for and the opening and closing and Gait. Edited by: A M BRONSTEIN, T sections of the book will scare oV many pos- The Neurobiology of Disease. BRANDT, AND M WOOLLACOTT. (Pp 350; sible readers. However, for those who are Contributions from Neuroscience to Clin- £85.00b). Published by Arnold, London prepared to do battle with these chapters the rewards are worth seeking, because the book ical Neurology. Edited by: H BOSTOCK, PA 1996. ISBN 0340601450. KIRKWOOD, AND A H PULLEN. (Pp 443; £65.00). does give one of the best overviews on the Published by Cambridge University Press, control of posture, balance, and locomotion This multiauthored book sets out to explore and with this comes an understanding of such Cambridge 1996. ISBN 0 521 45132 9. the neuroscientific basis, clinical examin- disorders as camptocormia, otolith Tullio ation, and evaluation of disorders of balance phenomenon, and Tumarrkin’s otolithic cri- It may seem a mighty task to produce a book and locomotion. The book has an opening sis. dealing with most of the major aspects of section on the organisation of the sensorimo- neurobiological research and its relevance to tor systems involved in balance, posture, and ROGER BARKER