Dr Fishman 121, should affect primarily the extracellular spaces o f white matter. Second, computerized tomography should reveal periventricular hypodensity associated with the edema [ 1,4, 5. 71, y e t to o u r knowledge none has been described in patients with pseudotumor cerebri. T h e reason or reasons for the abnormalities in tests of CSF absorption are unclear to us. It seems reasonable to suggest, however, that increased resistance to CSF outflow could develop setonduty to narrowing o r obliteration of the subarachnoid space d u e to the increase in brain bulk. T e m porary shrinking of brain, possibly with osmotic agents, would be expected to restore these tests to normal. Such a study has not yet been conducted but would b e helpful in clarifying the pathophysiology of pseudotumor cerebri. We agree with Dr Fishman that it is difficult to explain the proposed increase in brain water in pseudotumor cerebri. W e believe this reflects our limited understanding of the factors responsible for fluid homeostasis and cell volume regulation in the mammalian central nervous system. Precise control of brain volume, through adjustment of cell water and electrolyte content, is a complex phenomenon that is important for normal function not only because the brain is confined in a rigid and nondistensible skull, but also because changes in cell volume may normally affect important functional relationships between cells [8].This volume homeostasis must be achieved in the face of fluctuating osmotic and hydrostatic forces imposed by the incoming blood supply while respecting functionally critical ionic gradients within the brain. W e are certain that a satisfactory explanation of the pathophysiology of pseudotumor cerebri will emerge as our understanding of these complex interactions broadens.
Rebrences 1. Drayer BP, Rosenbaum AE, Riegel DB, et al: Metrizamide
-.7 3. 4.
5.
6.
7. 8.
computed tomography cisternography: pediatric application. Radiology 124:349-357, 1977 Fishman R A : Brain edema. N Engl J Med 293:706-711. 19’5 Morley JB, Reynolds EH: Papilledema and the LandryGuillain-Barre syndrome. Brain 89205-222, 1966 Naidich TP. Epstein F, Lin JP, et al: Evaluation of pediatric hydrocephalus by computed tomography. Radiology 1 19: 337-345, 19’6 Pasquini U. Bronzini M. Gozzoli E. et al: Periventricular hypodensity i n hydrocephalus. A clinical, radiological and mathematical analysis using computed tomography. J Comput Assist Tomogr 1:443-448. 1977 Ridsdale L. Mosley I: Thoracolumbar intraspinal tumors presenting features of raised intracranial pressure. J Neurol Neurosurg Psychiatry 41:737-745, 1978 Sahs AL, Joynr RJ: Brain swelling of unknown cause. Neurology (Minneap) 6:791-803, 1956 Van Harreveld A, Fifkova E: Swelling of dendritic spines in the facia dentara after stimulation of the perforant fibers as a mechanism of post-tetanic potentiation. Exp Neurol 49:736-749, 1975
Orthostatic Hypotension Pathology of the Disease D. R. Oppenheimer. DM Certain points in the article by Drs Petito and Black (Petito CK, Black IB: Ultrastructure and biochemistry of sympathetic ganglia in idiopathic orthostatic hypotension. Ann Neurol 4:6-17, 1978) deserve comment. T h e article is concerned with 4 patients, all suffering from orthostatic hypotension. This symptom may occur in several nervous system diseases I 3 I. T h e clinical and pathological details supplied by D r s Petito and Black arc insufficient. in each of the 4 cases, for a firm diagnosis; but there are striking variations in the 4 clinical accounts, indicating that the patients were suffering from different diseases. This difficulty is not overcome by labeling them all “idiopathic orthostatic hypotension.” If the authors wish to convince us that their 4 patients were suffering from the same disease, they should provide more in the way of pathological detail than, for instancc: ”Gross examination o f the brain showed mild to moderate atrophy and ventricular dilatation. Microscopic examination showed neuron loss and gliosis in many brainstem nuclei, including the substantia nigra and locus ceruleus.” T h e authors mention a paper by Bannister and O p penheimer [ I ] , the main point of which is that progressive autonomic failure d u e to degeneration of central autonomic pathways is associated with two well-recognized diseases: Parkinson’s disease, and multiple system atrophy of either striatonigral or olivopontocerebellar type. According to this view. which has been accepted by some investigators but not others, there is no .repurde disease entity to which the labels “idiopathic orthostatic hypotension” o r “Shy-Drager disease” can properly be applied. Drs Petito and Black d o not refute this view; they simply ignore it.
O n the question of cell loss in the intermediolateral columns (ILC) of the spinal cord, the authors display a startling degree of inconsistency. They write (page 13): ”The spinal intermediolateral cell columns appeared to contain a normal number of neurons in 1 patient, contained only mild gliosis in another, and exhibited moderate alteration in the remaining 2 patients. Morphometric examination of intermediolateral column neurons was not performed since a number of technical problems sometimes cause interpretative difficulties. This area is not well circumscribed in the longitudinal or horizontal plane, leading to gross sampling difficulties. Moreover, the distribution of neurons within the column might not b e random, and disease might alter neuronal and spinal cord volumes in an indeterminate manner. . . . To our knowledge these marked limitations have not been adequately addressed in previous studies 121“ (ref 1 1 1 in this letter). In view of these appalling difficulties, one wonders how the authors felt able to assess the “mild” or ”moderate” alterations in their patients’ cords. They d o not seem to
From thc Department of Neuropathology, The Radcliffe Infirmary, Oxford OX2 GHE, England.
Notes and Letters
497
have grasped: ( 1 ) that it is precisely bemuse o j irregular distribution, erc, that cell counting (which is presumably what they mean by “morphometric examination”) is n e e d e d ; ( 2 ) that there is no question o f establishingub~.o/lrten u m b e r s o f ILC cells; i t is merely a matter o f comparing patients with controls, and for this purpose it is sufficient to perform numerous counts in a consistent m a n n e r within an arbitrarily defined area; and ( 3 ) that t h e standard e r r o r s of t h e means so obtained a r e a g o o d indication of t h e d e g r e e of variability in t h e material examined. In their series, t h e authors clo not state t h e n u m b e r o f sections o n which their o w n estimates a r e based. T h e sampling difficulties referred to by the authors apply, if anything m o r e seriously. t o their estimations of histological changes in sympathetic ganglia. H e r e again. t h e authors d o not state t h e n u m b e r o f sections they examined o r how they controlled their findings. T h e y do, however, supply two illustrations. Figure 3 gives a low-power view (section thickness is not stated) of a sympathetic ganglion, showing n o obvious loss of cells but clear evidence of inflammation. Figure 4 shows a large eosinophilic body of a type characteristic o f Parkinson’s disease 121. T h e only valid inference from these pictures is that t h e 4 cases a r e n o t homogeneous. Neurochemistry and neuropharmacology are both rapidly cleveloping sciences. Advances in the latter a r e largely directed by advances in t h e former. T h e promise of effective treatments f o r degenerative diseases of the nervous system makes it incumbent o n investigators working o n clinical material t o m a k e sure that when they describe a series o f cases, they are in fact describing cases of t h e same condition; that is, like must b e compared with like. I t seems to me that nothing but confusion can arise from performing sophisticated biochemical procedures o n material from 4 apparently disparate cases and generalizing from t h e results.
Refe reti rr.c 1. Bannister R, Oppcnheimer DR: Degenerative diseases of the
nervous system associated with autonomic failure. Brain 9>:457-474. 1972 2. lager WA dcn H,Bethlem J: The distribution of Lewy bodies i n the ccntral and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23:283-290. 1060
3 . Johnsnn RH, Spalding J M K : Disorders ot the Autonomic Nervous Systcm. Oxford. England. Blackwell, 1973. chap 0
[ 1-41. Differentiation between these t w o conditions is o f t e n easy b u t is not always possible from clinical evaluation alone. N e r v e cell loss and t h e presence of Lewy bodies in pigmented nuclei o f the brainstem are generally regarded as diagnostic of IPA [ I , 41. Clinical features of parkinsonism are evident only after substantial loss of pigmented nerve cells in t h e subsrantia nigra, yet orthostatic hypotension may b e an early manifestation in s o m e patients with I P A 13, 41. In their paper, Patients 1 and 3 had pathological changes consistent with IPA. T h e clinical features o f hyperreflexia in Patient 1 w e r e likely d u e to recent o r old infarcts. At t h e present state o f knowledge in autonomic failure, w e think lumping together t h e t w o pathologically distinct entities should be avoided. 1h e r e has been considerable interest in Shy-Drager synd r o m e , but very few detailed reports have appeared o n autonomic failure in IPA. While t h e authors briefly commented o n s o m e reports dealing with severe orthostatic hypotension and sympathetic ganglion changes in IPA, they neglected to review o u r m o r e recent study that shows a quantitative correlation between orthostatic hypotension and abnormalities of the sympathetic ganglia in this condition 131. In t h e past t w o years w e have noted a similar clinicopatholoejcal association in 6 additional patients ( u n published observations). T h e authors have made an important observation. and w e compliment t h e m f o r their efforts. r .
Rrferetri-es 1. Bannister R: Degcnerarion of the autonomic nervous system. Lancet 2 : 1 7 5 - 1 7 0 , 1971 2. Davies B, Bannister R, Sever P: Pressor amines and mono-
ninine-cixidasc inhibitors for trwtnicnt of postural hypotension in autonomic failure. Lancet 1:172-175, 1978 3 . Rdjput Ail. Rozdilsky B: Dysauronom~ain pdrklnsonlsm. J Neurol Neurosurg Psychiatry 39:1092-1 100. 1976 1. Vandrrhaeghcn JJ, Perier 0, Sternon JE: Pathological findinys i n idiopathic orthostatic hypotension. Arch Neurol 22:207214. 1970
Reply Ira B . Black, MD, and Carol K. Petito, M D
T h e paper by Drs Petito and Black gives t h e impression that all patients with idiopathic orthostatic hypotension (]OH)suffer from Shy-Drager syndrome (multiple system atrophy with orthostatic hypotension). Orthostatic hypotension may b e a m a j o r feature of idiopathic paralysis agitans ( I P A ) as well-another distinct pathological entity
W e thank t h e correspondents for their comments and agree that it is particularly difficult to classify, or subclassify, syndromes f o r which biochemical, ultrastructural, pathogenetic, and etiological analysis is inadequate. Although all our patients suffered from primary autonomic failure as indicated by clinical histories and laboratory tests, pathological changes w e r e variable, attesting to t h e spectrum o f this disease and t h e need f o r precise biochemical evaluation. As indicated by D r O p p e n h e i m e r , only s o m e authors accept his particular subclassification. O n the o t h e r hand, Drs Rajput and Rozdilsky agree that differentiation between their t w o subclassifications is “ n o t always possible.”
From t h c 1)epartment ot Clinical Neurological Sciences, C n i v e r city 1 ~ospit.iI,Saskatoon, Saskatchewan. Canada S7N OW8.
From the Departments of Neurology and Pathology, Cornell University Medical College. New York, N Y 10021.
Sympathetic Ganglia Changes A . ti. Ralput, FRCI’(C), and H. RozdilsLy, P h D , F R C P ( C )
498
Annals of Neurology
Vol 5
No 5
May 19’9
Rebrences 1. Drayer BP, Rosenbaum AE, Riegel DB, et al: Metrizamide
-.7 3. 4.
5.
6.
7. 8.
computed tomography cisternography: pediatric application. Radiology 124:349-357, 1977 Fishman R A : Brain edema. N Engl J Med 293:706-711. 19’5 Morley JB, Reynolds EH: Papilledema and the LandryGuillain-Barre syndrome. Brain 89205-222, 1966 Naidich TP. Epstein F, Lin JP, et al: Evaluation of pediatric hydrocephalus by computed tomography. Radiology 1 19: 337-345, 19’6 Pasquini U. Bronzini M. Gozzoli E. et al: Periventricular hypodensity i n hydrocephalus. A clinical, radiological and mathematical analysis using computed tomography. J Comput Assist Tomogr 1:443-448. 1977 Ridsdale L. Mosley I: Thoracolumbar intraspinal tumors presenting features of raised intracranial pressure. J Neurol Neurosurg Psychiatry 41:737-745, 1978 Sahs AL, Joynr RJ: Brain swelling of unknown cause. Neurology (Minneap) 6:791-803, 1956 Van Harreveld A, Fifkova E: Swelling of dendritic spines in the facia dentara after stimulation of the perforant fibers as a mechanism of post-tetanic potentiation. Exp Neurol 49:736-749, 1975
Orthostatic Hypotension Pathology of the Disease D. R. Oppenheimer. DM Certain points in the article by Drs Petito and Black (Petito CK, Black IB: Ultrastructure and biochemistry of sympathetic ganglia in idiopathic orthostatic hypotension. Ann Neurol 4:6-17, 1978) deserve comment. T h e article is concerned with 4 patients, all suffering from orthostatic hypotension. This symptom may occur in several nervous system diseases I 3 I. T h e clinical and pathological details supplied by D r s Petito and Black arc insufficient. in each of the 4 cases, for a firm diagnosis; but there are striking variations in the 4 clinical accounts, indicating that the patients were suffering from different diseases. This difficulty is not overcome by labeling them all “idiopathic orthostatic hypotension.” If the authors wish to convince us that their 4 patients were suffering from the same disease, they should provide more in the way of pathological detail than, for instancc: ”Gross examination o f the brain showed mild to moderate atrophy and ventricular dilatation. Microscopic examination showed neuron loss and gliosis in many brainstem nuclei, including the substantia nigra and locus ceruleus.” T h e authors mention a paper by Bannister and O p penheimer [ I ] , the main point of which is that progressive autonomic failure d u e to degeneration of central autonomic pathways is associated with two well-recognized diseases: Parkinson’s disease, and multiple system atrophy of either striatonigral or olivopontocerebellar type. According to this view. which has been accepted by some investigators but not others, there is no .repurde disease entity to which the labels “idiopathic orthostatic hypotension” o r “Shy-Drager disease” can properly be applied. Drs Petito and Black d o not refute this view; they simply ignore it.
O n the question of cell loss in the intermediolateral columns (ILC) of the spinal cord, the authors display a startling degree of inconsistency. They write (page 13): ”The spinal intermediolateral cell columns appeared to contain a normal number of neurons in 1 patient, contained only mild gliosis in another, and exhibited moderate alteration in the remaining 2 patients. Morphometric examination of intermediolateral column neurons was not performed since a number of technical problems sometimes cause interpretative difficulties. This area is not well circumscribed in the longitudinal or horizontal plane, leading to gross sampling difficulties. Moreover, the distribution of neurons within the column might not b e random, and disease might alter neuronal and spinal cord volumes in an indeterminate manner. . . . To our knowledge these marked limitations have not been adequately addressed in previous studies 121“ (ref 1 1 1 in this letter). In view of these appalling difficulties, one wonders how the authors felt able to assess the “mild” or ”moderate” alterations in their patients’ cords. They d o not seem to
From thc Department of Neuropathology, The Radcliffe Infirmary, Oxford OX2 GHE, England.
Notes and Letters
497
have grasped: ( 1 ) that it is precisely bemuse o j irregular distribution, erc, that cell counting (which is presumably what they mean by “morphometric examination”) is n e e d e d ; ( 2 ) that there is no question o f establishingub~.o/lrten u m b e r s o f ILC cells; i t is merely a matter o f comparing patients with controls, and for this purpose it is sufficient to perform numerous counts in a consistent m a n n e r within an arbitrarily defined area; and ( 3 ) that t h e standard e r r o r s of t h e means so obtained a r e a g o o d indication of t h e d e g r e e of variability in t h e material examined. In their series, t h e authors clo not state t h e n u m b e r o f sections o n which their o w n estimates a r e based. T h e sampling difficulties referred to by the authors apply, if anything m o r e seriously. t o their estimations of histological changes in sympathetic ganglia. H e r e again. t h e authors d o not state t h e n u m b e r o f sections they examined o r how they controlled their findings. T h e y do, however, supply two illustrations. Figure 3 gives a low-power view (section thickness is not stated) of a sympathetic ganglion, showing n o obvious loss of cells but clear evidence of inflammation. Figure 4 shows a large eosinophilic body of a type characteristic o f Parkinson’s disease 121. T h e only valid inference from these pictures is that t h e 4 cases a r e n o t homogeneous. Neurochemistry and neuropharmacology are both rapidly cleveloping sciences. Advances in the latter a r e largely directed by advances in t h e former. T h e promise of effective treatments f o r degenerative diseases of the nervous system makes it incumbent o n investigators working o n clinical material t o m a k e sure that when they describe a series o f cases, they are in fact describing cases of t h e same condition; that is, like must b e compared with like. I t seems to me that nothing but confusion can arise from performing sophisticated biochemical procedures o n material from 4 apparently disparate cases and generalizing from t h e results.
Refe reti rr.c 1. Bannister R, Oppcnheimer DR: Degenerative diseases of the
nervous system associated with autonomic failure. Brain 9>:457-474. 1972 2. lager WA dcn H,Bethlem J: The distribution of Lewy bodies i n the ccntral and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23:283-290. 1060
3 . Johnsnn RH, Spalding J M K : Disorders ot the Autonomic Nervous Systcm. Oxford. England. Blackwell, 1973. chap 0
[ 1-41. Differentiation between these t w o conditions is o f t e n easy b u t is not always possible from clinical evaluation alone. N e r v e cell loss and t h e presence of Lewy bodies in pigmented nuclei o f the brainstem are generally regarded as diagnostic of IPA [ I , 41. Clinical features of parkinsonism are evident only after substantial loss of pigmented nerve cells in t h e subsrantia nigra, yet orthostatic hypotension may b e an early manifestation in s o m e patients with I P A 13, 41. In their paper, Patients 1 and 3 had pathological changes consistent with IPA. T h e clinical features o f hyperreflexia in Patient 1 w e r e likely d u e to recent o r old infarcts. At t h e present state o f knowledge in autonomic failure, w e think lumping together t h e t w o pathologically distinct entities should be avoided. 1h e r e has been considerable interest in Shy-Drager synd r o m e , but very few detailed reports have appeared o n autonomic failure in IPA. While t h e authors briefly commented o n s o m e reports dealing with severe orthostatic hypotension and sympathetic ganglion changes in IPA, they neglected to review o u r m o r e recent study that shows a quantitative correlation between orthostatic hypotension and abnormalities of the sympathetic ganglia in this condition 131. In t h e past t w o years w e have noted a similar clinicopatholoejcal association in 6 additional patients ( u n published observations). T h e authors have made an important observation. and w e compliment t h e m f o r their efforts. r .
Rrferetri-es 1. Bannister R: Degcnerarion of the autonomic nervous system. Lancet 2 : 1 7 5 - 1 7 0 , 1971 2. Davies B, Bannister R, Sever P: Pressor amines and mono-
ninine-cixidasc inhibitors for trwtnicnt of postural hypotension in autonomic failure. Lancet 1:172-175, 1978 3 . Rdjput Ail. Rozdilsky B: Dysauronom~ain pdrklnsonlsm. J Neurol Neurosurg Psychiatry 39:1092-1 100. 1976 1. Vandrrhaeghcn JJ, Perier 0, Sternon JE: Pathological findinys i n idiopathic orthostatic hypotension. Arch Neurol 22:207214. 1970
Reply Ira B . Black, MD, and Carol K. Petito, M D
T h e paper by Drs Petito and Black gives t h e impression that all patients with idiopathic orthostatic hypotension (]OH)suffer from Shy-Drager syndrome (multiple system atrophy with orthostatic hypotension). Orthostatic hypotension may b e a m a j o r feature of idiopathic paralysis agitans ( I P A ) as well-another distinct pathological entity
W e thank t h e correspondents for their comments and agree that it is particularly difficult to classify, or subclassify, syndromes f o r which biochemical, ultrastructural, pathogenetic, and etiological analysis is inadequate. Although all our patients suffered from primary autonomic failure as indicated by clinical histories and laboratory tests, pathological changes w e r e variable, attesting to t h e spectrum o f this disease and t h e need f o r precise biochemical evaluation. As indicated by D r O p p e n h e i m e r , only s o m e authors accept his particular subclassification. O n the o t h e r hand, Drs Rajput and Rozdilsky agree that differentiation between their t w o subclassifications is “ n o t always possible.”
From t h c 1)epartment ot Clinical Neurological Sciences, C n i v e r city 1 ~ospit.iI,Saskatoon, Saskatchewan. Canada S7N OW8.
From the Departments of Neurology and Pathology, Cornell University Medical College. New York, N Y 10021.
Sympathetic Ganglia Changes A . ti. Ralput, FRCI’(C), and H. RozdilsLy, P h D , F R C P ( C )
498
Annals of Neurology
Vol 5
No 5
May 19’9
