Schizophrenia
and Amyotrophic
Lateral Sclerosis
Robert H. Howland Schizophrenia and amyotrophic lateral sclerosis (AL% are central nervous system KNS) disorders of unknown etiology. The association of these two disorders has been infrequently reported in the literature, but is not a rare occurrence. Various neuromuscular abnormalities involving the alpha-motor neuron have been described in some patients with schizophrenia. This report reviews the literature on schizophrenia, psychosis, and ALS and describes two additional cases of schizophrenia associated with ALS. The possibility that the neuromuscular dysfunction in schizophrenia may predispose to ALS and provide an explanation for the association of these two disorders is discussed. Additional research data are needed to test this hypothesis. 0 1990 by W. B. Saunders Company.
HE ETIOLOGY and pathophysiology of schizophrenia remain an enigma. However, although it has been characterized historically as a “functional” disorder, there is ever-increasing evidence that biochemical, neuroanatomical, and other organic factors are in fact involved. Many organic cerebral disorders have been found to be associated with schizophrenia-like psychoses, often indistinguishable clinically from functional schizophrenia.’ Amyotrophic lateral sclerosis (ALS), a motor system disorder, has been infrequently reported in the literature to be associated with schizophrenia or other psychoses. Although these disorders presumably affect different aspects of the central nervous system (CNS), each may manifest both motor and cognitive symptoms. Moreover, many similar factorsgenetic, viral, toxic-metabolic, and immunologic-have been implicated in their pathophysiology. This report will review the literature on schizophrenia, psychosis, and ALS, describe two cases of long-standing schizophrenia with the later onset of ALS, and discuss some of the implications of this association. ALS is a progressive degenerative syndrome of unknown etiology involving the upper and lower (alpha) motor neuron systems and is characterized clinically by muscle weakness, spasticity, hyperreflexia, fasciculations, muscle atrophy, dysarthria, and dysphagia. The specific clinical pattern of signs and symptoms may vary depending on the motor system, which is predominately affected. The terms progressive muscular atrophy (spinal alpha-motor neuron involvement), progressive bulbar palsy (brainstem alpha-motor neuron involvement), primary lateral sclerosis (corticospinal tract involvement), and progressive pseudobulbar palsy (corticobulbar tract involvement) have been used to describe them.* The term motor neuron disease (MND) has also been used generically to describe the spectrum of disorders affecting motor neurons. Ultimately, the symptoms progress to a final common state of total motor debilitation. Greater than 90% of cases are sporadic, although familial and juvenile cases are well described.3 The average annual incidence rate ranges from 0.4 to 1.8 per 100,000 population, the prevalence rate ranges from 4 to 6 per 100,000 population, and there is a slight male predominance.2 The average age
T
From the Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine. Pittsburgh, PA. Address reprint requests to Robert H. Howland. M.D., Room 24, 381 I O’Hara St, Pittsburgh, PA 15213. Q 1990 by W.B. Saunders Company.
0010-440x/90/31 04-0003%03.00/0 Comprehensive Psychiatry, Vol. 3 1, No. 4 (July/August), 1990: pp 327-336
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of onset is 50 to 60 years, although the range is quite large, and death typically occurs within 5 years.4 Although ALS is classically described as a motor system disorder, there are a significant number of reports in the literature describing the occurrence of a variety of mental symptoms in association with ALS. The most commonly reported mental symptoms are cognitive changes and dementia. Dementia is reported to occur in up to 5% of cases of ALS’ and is well described in the parkinsonism-dementia-ALS complex of the Western Pacific5*6 and in a new entity, presenile dementia with MND.’ A syndrome characterized by ALS with a rapidly progressive dementia resembling Creutzfeldt-Jakob disease has been described,5,8y9although it is probably not transmissible.” A few cases of ALS with temporal lobe abnormalities and a dementia resembling Pick’s disease have also been described.11~12Finally, neuropsychological abnormalities without clinical evidence of dementia have been reported,‘3v’4 but these findings have not been supported by other studies.15 Emotional lability, characterized by pathological laughing and crying, frequently occurs in ALS, especially in cases with prominent bulbar or pseudobulbar symptoms.16-18Depression is felt to be commonly associated with ALS, although the incidence is unknown.2*‘6.19,20 Ho wever, other studies using personality inventories to assess patients with ALS have suggested a distinctive personality profile characterized by an unusually cheerful attitude,*l active mastery, and denial of depressive/ anxious feelings. **These findings were not supported by another study.23 In contrast to the cognitive impairment and affective symptoms described above, psychotic symptoms have been reported in association with ALS much less commonly. Ziegler16 reviewed some of the earliest reports in the European literature of psychosis in ALS and reported three cases of his own. In his review he cited a case reported by Fragnito (1907) that was “possibly affected with hallucinosis” (p. 630)i6 and a case reported by Pilcz (1908) of “a patient with persecutory ideas and hallucinations” (p. 63 1).16His own three cases included one in which the symptoms of psychosis preceded the onset of ALS by 3 years. Wechsler and DavisonI reviewed much of the same early literature on ALS and psychosis, but also cited the work of Van Bogaert (1925) who had reported on 10 of 31 cases of ALS with “characteristic psychotic disturbances” (p. 878).17 In addition, they described three cases of ALS that had postmortem neuropathological examinations; each patient had exhibited a psychosis that was felt to be due to the underlying neuropathology found in their study. They concluded that most cases of ALS are without psychotic manifestations, that those cases with psychosis are most likely to be coincidentally associated with functional psychotic disorders, and that in some cases of ALS the psychosis is related to an underlying cerebral pathological process that is a part of ALS. Androp described a case in which paranoid ideation was present for approximately 18 years before the diagnosis of ALS; the patient later developed auditory hallucinations and finally dementia before his death. Like Wechsler and Davison, Androp felt that the psychosis in this case was related to the underlying neuropathological changes that were noted at autopsy, although it is significant that the delusional thoughts preceded the onset of motor symptoms by a very long period of time. In a brief review of MND and schizophrenia-like psychoses, Davison and Bagleylg cited additional reports in the European literature by Westphal (1925),
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Recktenwald (1920), and Raithel (1941). Westphal (1925) described two patients with ALS who later developed paraphrenia phantastica and paranoid schizophrenia. Recktenwald (1920) reported a case of two sisters with progressive muscular atrophy who both later developed schizophrenia-like psychotic disorders. Raithel ( 194 1) described a case of schizophrenia that preceded the onset of ALS by some years. Meller25 reported a case of ALS with a paranoid type of psychosis and euphoria. Riley and Tirico26 described a case of ALS occurring in a patient who had hebephrenic schizophrenia for many years. Friedlander and Kesert27 presented a case of ALS with dementia and psychosis; the psychosis apparently was manifested by emotional lability and irrational and peculiar behavior. In the recent literature, Yvonneau2s reported an unusual case of paranoid schizophrenia complicated by a hypokalemic syndrome that was felt to be causally related to the later onset of ALS. Yase et a1.29described an interesting patient who had schizophrenic symptoms for 7 years before the onset of ALS. The postmortem neuropathological examination was remarkable for the presence of neurofibrillary tangles, although cognitive deficits were not noted in the clinical report. Finally, Burnstein3’ described an interesting family with an unusual constellation of neurological and psychiatric illnesses. One patient had a long-standing history of a schizophrenia-like illness and later developed ALS followed by dementia. An assessment of 36 extended family members over four generations demonstrated 13 persons with a variety of neurological and/or psychiatric illnesses, including ALS, dementia, Parkinson’s disease, brain tumor, epilepsy, schizophrenia-like and affective psychoses, and melancholia. This review appears to show that many patients with ALS will manifest psychotic symptoms, if present, shortly before or during the period of motor symptoms.‘6*‘9~25q27 In other patients, a psychotic disorder precedes the clinical syndrome by a longer Notable, also, is that the concept of psychosis as used by period of time. 16~19,24V26,29,30 some of the authors is not well defined. In many cases the reported psychotic symptoms may be indistinguishable from a dementia, delirium, or other organic psychosis directly related to the CNS pathology of ALS; other cases clearly demonstrate what may be regarded as true functional psychoses in association with the later development of ALS. Two cases of long-standing schizophrenia with the late onset of ALS will now be presented and some implications of this association will be discussed. CASE REPORTS Case 1 Mr. A was a 39-year-old white man with a 14-year history of chronic paranoid schizophrenia when he initially presented for a neurological evaluation in 1986 with the complaint of muscle stiffness, difficulty swallowing, and difficulty talking of at least 4 months’ duration. He stated that he had experienced a sudden weakness in his left side approximately 1 month before his presentation, but did not seek medical attention. He felt that it had improved since that time. He had no other significant medical history, including drug or alcohol use. During the recent past he apparently had more frequent relapses and rehospitalizations with poor functioning overall. Mr. A’s neurological evaluation (including a computed tomography [CT] scan, electromyogram [EMG] study, and muscle biopsy) was consistent with a right hemisphere cerebrovascular accident and ALS. His subsequent course was marked by a rapid deterioration in his functioning and health, although he suffered no apparent recurrence of his psychosis. He died 10 months later of an aspiration pneumonia. An autopsy study was remarkable for brain
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atrophy, rarefaction of the corticospinal tracts within the spinal cord, and small hyperchromatic motor neurons, consistent with the clinical diagnosis.
Case 2 Mr. B was a 50-year-old white man with a 30-year history of chronic paranoid schizophrenia when he initially presented for a neurological evaluation in 1986 with a complaint of muscle “twitches” in his arms and legs and difficulty walking for 4 months. He had no significant medical history, including drug or alcohol use. His neurological evaluation (including an magnetic resonance image [MRI] scan and EMG study) was consistent with ALS. Mr. B’s neurological illness progressed rapidly and he died 1 year after his diagnosis. An autopsy was not performed.
DISCUSSION
These two cases of ALS were characterized by an associated schizophrenia existing 14 years and 30 years, respectively, before the development of the MND. There were no other known physical conditions to account for the psychotic and neuromuscular symptoms; although the first patient also had suffered a recent cerebrovascular accident, there was no evidence relating it to either the psychosis or the neuromuscular abnormalities. Whenever two CNS disorders are found to exist in the same patient, it would be of clinical and scientific interest to know whether there is causal relationship between the two conditions, if they have a common etiology, or if they merely coexist by a chance association. The implications of such an association are important to consider, not only because they may provide valuable insights into the etiology and pathophysiology of the coexistent disorders or related conditions, but also because additional aspects of the clinical picture and natural history of the disorders may be identified. In those cases of ALS reviewed above, in which the psychosis occurs shortly before or during the course of the neuromuscular symptoms, it would be reasonable to conclude that the psychosis is organic in nature and related to the underlying pathological CNS process of ALS.‘6~‘g~25~27 In support of this are those cases in which the neuropathological findings demonstrate diffuse CNS changes extending beyond the classically defined abnormalities of the motor nuclei and corticospinal tracts.‘7*24V2g Also, extensive CNS abnormalities have been well described in other neuropathologmaking it quite possible that impairment of other CNS ical studies of ALS,5V31V32 functioning in ALS may occur in addition to the motor dysfunction. When a presumed functional psychotic disorder, such as schizophrenia, exists in a patient who later develops ALS (often years apart, since the average age of onset of schizophrenia is much earlier than that of ALS), it would be difficult to demonstrate that a causal relationship exists or that there is a common etiology for the two disorders. This is especially so when the etiology and pathophysiology are unknown and biological markers do not exist for these disorders. To determine a possible linkage would then depend on the demonstration that ALS occurred more frequently in a population with schizophrenia than in a normal control population or, conversely, that a history of schizophrenia is more frequent in a population with ALS than in a normal control population. Baldwin33 has described the various methodological issues and problems encountered in using population studies to assess the relationship between physical disease and schizophrenia. When one or both disorders have a relatively low incidence and prevalence, as with ALS, a large number of patienrs, and a thorough ascertainment of cases, would be needed to show a greater than expected chance of association. In addition, the excess mortality and
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premature death found in schizophrenia34 may effectively reduce the number of cases of schizophrenia that reach the ages of highest risk for the development of ALS, unless it can be demonstrated that ALS itself accounts for some of the excess mortality. To my knowledge, no epidemiological studies have been conducted that have specifically examined the incidence and prevalence of ALS in schizophrenia or systematically assessed the psychiatric history in ALS. Although various neurological signs and symptoms have been well described in a large percentage of persons with schizophrenia, they are generally regarded as nonspecific. Very little information is available in the literature that describes specific neurological syndromes, such as ALS, or examines the progression of the neurological abnormalities in schizophrenia over time.35 Exceptions to this are the well-known problems of tardive dyskinesia and other extrapyramidal syndromes. Many studies have examined the mortality rate and cause of death in schizophrenia, focusing primarily on such categories of morbidity as infectious disease, cancer, cardiovascular disorders, accidents, and suicide. Those studies that also include a category of conditions affecting the nervous system generally have not specified particular neurological disorders or report only such major conditions as brain neoplasms and cerebrovascular disease. As a result, there is little data to address the issue of the incidence and prevalence of ALS in schizophrenia. However, Mettler and Crandel136 were specifically interested in the incidence of neurological disorders in an institutionalized psychiatric population. In their meticulous assessment of 5,704 patients they found five cases of progressive pseudobulbar palsy and at least one case each of ALS and bulbar palsy (the authors did not specify the exact numbers). These seven cases of MND would suggest an estimated prevalence of MND in this institution of approximately 120 per 100,000 population, a rate considerably higher than most estimates in the general population. These results cannot necessarily be generalized to schizophrenia, because the study population consisted of both functional and organic disorders and the specific diagnoses of the patients with MND are not reported. Nevertheless, these findings suggest that if a careful assessment is done, MND may be present more often than expected in a chronically ill psychiatric population. Additional study in other psychiatric populations is warranted. An alternate method of studying the association between schizophrenia and ALS is to assess the psychiatric history of a group with ALS. As with schizophrenia, a large number of epidemiological studies of ALS have been performed and many have included data on various associated physical conditions. However, few of these studies report on the psychiatric history of their subjects. Jokelainen37 investigated 255 cases of ALS in Finland and found that 14 (5%) had a history of “psychiatric disorder or mental retardation.” This finding is difficult to interpret since specific diagnoses were not reported and there was no control population to determine whether this percentage was significantly different than expected. In a case-control study, Kurtzke and Beebe38 found 51 cases of “mental disorders” (the diagnoses were unspecified) in a cohort of 504 veterans with ALS and 45 cases in a control group of 504 veterans without ALS. The difference was not significant. However, as designed, this study could not adequately address the issue of the psychiatric history in ALS for two reasons. First, the subjects were selected for the presence or absence of ALS and incomplete military service record abstracts were examined retrospec-
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tively for any psychiatric disorders noted only at the time of induction into military service or during the period of their military service. Thus, many psychiatric conditions were likely to be missed. Second, persons who would otherwise have been eligible for induction into the service, and might later develop ALS, may have been rejected due to a preexisting mental disorder, especially a disorder of early onset such as schizophrenia. Therefore, assuming that schizophrenia would be only one of multiple antecedents of ALS, this particular study population would be biased against including cases associated with schizophrenia, making it difficult to determine if schizophrenia is indeed associated with ALS. Finally, Forsgren et al.3g reported only one subject with schizophrenia out of 128 cases of ALS in northern Sweden, but their study was not intended to look for disorders associated with ALS. As can be seen from the available epidemiological data, no firm conclusions can be made as to the significance of the psychiatric history in ALS. Given the paucity of information that exists in the epidemiological literature of both schizophrenia and ALS that pertains to their possible association, the issue cannot be definitively resolved. However, other clinical and experimental evidence exists that may be relevant to a consideration of the coexistence of these two disorders. As discussed above, schizophrenia is often associated with a variety of neurological abnormalities, generally with a prevalence greater than that of other psychiatric disorders and nonpsychiatric controls. 35These abnormalities would be of particular relevance in this regard if they included abnormalities of the neuromuscular system as well. In fact, various abnormalities of the neuromuscular system have been described in some psychotic disorders, although this has been studied most extensively in schizophrenia. 40-43Serum creatine phosphokinase (CPK), derived from skeletal muscle, has been shown to be elevated in many patients during acute episodes of psychosis. 40*44,45 CPK may also be relatively elevated during nonacute phases of the illness and in first-degree relatives of schizophrenics.40*42 Skeletal muscle biopsy specimens from some patients with schizophrenia have shown a variety of morphological abnormalities,43346 which have been noted in some of their firstdegree relatives also. 40,44Increased branching of subterminal motor neurons (the most distal region of the alpha-motor neuron proximal to the motor endplate) has been described in patients43 and first-degree relatives,40 suggesting a process of motor neuron degeneration and regeneration.44347*48Electrophysiological studies have demonstrated abnormalities of the alpha-motor neuron and motor unit that are Some of these abnormalities consistent with denervation and reinnervation. 41946V4g also have been found in first-degree relatives. So Finally, abnormalities of the Hoffman reflex (H-reflex) have been described.40V41351-53 The H-reflex is an electrically evoked monosynaptic spinal cord reflex that provides an index of alpha-motor neuron excitability. Therefore, the abnormalities of the H-reflex in these studies are an indication of altered alpha-motor neuron excitability in schizophrenia. These abnormalities are felt to be most consistent with a neurogenic, rather than They have been found to persist during the course of the myopathic, process. 44,48V4g illness, irrespective of such factors as age, duration of illness, number of psychotic episodes, frequency of hospitalization, medication use, intercurrent physical illness, although long-term follow-up has not been reported. There is or drug abuse, 40*4’s46 some evidence that the H-reflex may differ in acute and chronic patients, suggesting
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that the neuromuscular abnormality may be related to the chronicity of the illness. 40,41351-53 The cause of these neuromuscular abnormalities in schizophrenia is unknown, although it has been postulated that they may result from some type of endogenous substance toxic to alpha-motor neurons,40’48some intrinsic alpha-motor neuron pathology,40 a supraspinal CNS derangement with an altered neurotrophic influence on the alpha-motor neuron,48,51a generalized cell membrane or neuronal defect,46 or central neurotransmitter abnormalities. 46*51-53 In addition, that these findings exist in some first-degree relatives suggests a genetic diathesis. The clinical significance of these abnormalities in schizophrenia has not been systematically studied and is unknown. It has been suggested that they may contribute to the vulnerability to psychosis,42 the neuromotor dysfunction found in schizophrenia (such as abnormal eye-tracking),40*44 and the disordered motor development and function seen in children of schizophrenics.42*46 However, these neuromuscular abnormalities also strongly imply an ill-defined dysfunction of the alpha-motor neuron in schizophrenia. Furthermore, all have been described in ALS as we11.2’4It is conceivable that the association of schizophrenia and ALS as described in these case reports and in the literature may not be coincidental and may be understood on the basis of these neuromuscular abnormalities. This hypothesis suggests that the neuromuscular dysfunction in schizophrenia represents an abnormality of the alpha-motor neuron and that this abnormality may predispose at least some patients with schizophrenia to the later development of ALS, since the diseased alpha-motor neuron is a sine qua non of ALS. How this abnormality arises is open to speculation. Genetic, toxic-metabolic, and immunologic factors, implicated in both disorders, remain unproven. One possibility of particular interest is the role of central neurotransmitters. Various central neurotransmitter abnormalities are noted in schizophrenias4 and have also been described in ALS.55-58 In addition, neurotransmitter receptors exist in the spinal cord, including the anterior horn, and alterations in these have been described in ALS.49sgX60 Altered central neurotransmission, such as increased dopamine, may adversely affect the alpha-motor neuron,5’-53*6’causing injury to it directly or rendering it susceptible to injury from another insult. In this scenario, abnormal neurotransmitter levels in some schizophrenics may be a potential mechanism of alpha-motor neuron injury leading to ALS. The possibility that injury to the peripheral nervous system can occur by such an altered central neurotrophic effect has been described elsewhere.62*63 Moreover, altered neurotrophism has been suggested as a unifying concept to explain the neurodegeneration in Alzheimer’s disease, Parkinson’s disease, and ALS64 and would be consistent with this hypothesis. Ultimately, whether the coexistence of these two disorders is the result of a common etiological factor or is due to some other factor associated with schizophrenia that renders them susceptible to ALS cannot be determined with the available data. Also, whether the neuromuscular abnormality in schizophrenia is a primary or secondary phenomenon cannot be definitively resolved. However, this type of abnormality does suggest a potential biological link between schizophrenia and ALS, a disorder affecting the motor neuron. Since the neuromuscular abnormalities are not present in all schizophrenics, and the severity may vary, it is not likely that ALS would be a common clinical sequela of schizophrenia. Further investigation of
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the association of schizophrenia and ALS would require larger numbers of patients, comprehensive neurological evaluations in schizophrenia with particular attention to neuromuscular disorders (especially in older chronically ill schizophrenics), long-term prospective follow-up of schizophrenics with and without the neuromuscular abnormalities described above, additional laboratory studies to better characterize these findings, and postmortem neuropathological studies of the spinal cord in schizophrenia. The benefit of further investigations in this area would be to acquire additional knowledge of the systemic abnormalities and novel clinical features of the schizophrenic syndrome, better characterize the natural history of schizophrenia, and develop new insights into the etiology and pathophysiology of ALS and other neuromuscular disorders. ACKNOWLEDGMENT The author would like to thank Karen Neal for her work in the preparation of the manuscript.
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CNS: A review of the literature, in Herrington RN (ed): Current Problems in Neuropsychiatry. British Journal of Psychiatry Special Publication no 4, 1969, p 139 20. Lishman WA: Organic Psychiatry: The Psychological Consequences of Cerebral Disorder (ed 2). Oxford, England, Blackwell Scientific, 1987, pp 603-605 21. Veit H: Dynamic view of amyotrophic lateral sclerosis. J Nerv Ment Dis 106:129-136, 1947 22. Brown WA, Mueller PS: Psychological function in individuals with amyotrophic lateral sclerosis (ALS). Psychosom Med 32:141-152,197O 23. Peters PK, Swenson WM, Mulder DW: Is there a characteristic personality profile in amyotrophic lateral sclerosis? Arch Neurol35:321-322, 1978 24. Androp S: Amyotrophic lateral sclerosis with psychosis. Psychiatr Q 14:8 18-825, 1940 25. Meller C: Amyotrophic lateral sclerosis with psychosis, paranoid type. Minn Med 23:858-859, 1940 26. Riley WK. Tirico JG: Amyotrophic lateral sclerosis occurring in dementia praecox. M Bull Vet Admin 17:180-181, 1940 27. Friedlander JW, Kesert BH: The role of psychosis in amyotrophic lateral sclerosis. J Nerv Ment Dis 107:243-250, 1948 28. Yvonneau M: Schizophrenic psychosis, hypokalemic paralysis, and amyotrophic lateral sclerosis. Ann Med Psycho1 127:701,1969 29. Yase Y, Matsumoto N, Azuma K, et al: Amyotrophic lateral sclerosis: Association with schizophrenic symptoms and showing Alzheimer’s tangles. Arch Neurol27: 118- 128, 1972 30. Burnstein MH: Familial amyotrophic lateral sclerosis, dementia and psychosis. Psychosomatics 22:151-157, 1981 31. Smith MC: Nerve fibre degeneration in the brain in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 23:269-282, 1960 32. Brownell B, Oppenheimer DR, Hughes JT: The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry 33:338-357, 1970 33. Baldwin JA: Schizophrenia and physical disease. Psycho1 Med 9:611-618, 1979 34. Black DW: Mortality in schizophrenia-The Iowa record-linkage study: A comparison with general population mortality. Psychosomatics 29:55-60, 1988 35. Heinrichs DW, Buchanan RW: Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry 145:l I-18, 1988 36. Mettler FA, Crandell A: Neurologic disorders in psychiatric institutions. J Nerv Ment Dis 128:148-159, 1959 37. Jokelainen M: Amyotrophic lateral sclerosis in Finland. II: Clinical characteristics. Acta Neurol Stand 56: 194-204, 1977 38. Kurtzke JF, Beebe GW: Epidemiology of amyotrophic lateral sclerosis: l.A case-control comparison based on ALS deaths. Neurology 30:453-462, 1980 39. Forsgren L, Almay BGL, Holmgren G, et al: Epidemiology of motor neuron disease in northern Sweden. Acta Neurol Stand 68:20-29, 1983 40. Meltzer HY: Neuromuscular dysfunction in schizophrenia. Schizophr Bull 2:106-135, 1976 41. Goode DJ, Meltzer HY, Crayton JW, et al: Physiologic abnormalities of the neuromuscular system in schizophrenia. Schizophr Bull 3:121-138, 1977 42. Meltzer HY, Goode DJ, Arora RC: Neuromuscular dysfunction and vulnerability to psychosis. Psychopharmacol Bull 15:43-44, 1979 43. Ross-Stanton J, Schlessinger S, Meltzer HY: Multiple neuromuscular abnormalities in a paranoid schizophrenic. Psychiatry Res 3:53-67, 1980 44. Meltzer HY, Crayton JW: Muscle abnormalities in psychotic patients, II. Serum CPK activity, fiber abnormalities, and branching and sprouting of subterminal nerves. Biol Psychiatry 8:191-208, 1974 45. Meltzer HY: Neuromuscular abnormalities in the major mental illnesses. 1. Serum enzyme studies, in Freedman DX (ed): The Biology of the Major Psychoses: A Comparative Analysis. New York. NY, Raven, 1975, pp 165- I88 46. Borg J, Edstrom L, Bjerkenstedt L, et al: Muscle biopsy findings, conduction velocity and refractory period of single motor nerve tibres in schizophrenia. J Neurol Neurosurg Psychiatry 50:1655-1664, 1987 47. Crayton JW, Meltzer HY: Motor endplate alterations in schizophrenic patients. Nature 264~658-659. 1976
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48. Crayton JW, Meltzer HY: Degeneration and regeneration of motor neurons in psychotic patients. Biol Psychiatry 14:803-819, 1979 49. Crayton JW, Stalberg E, Hilton-Brown P: The motor unit in psychotic patients: A single fibre EMG study. J Neural Neurosurg Psychiatry 40:455-463, 1977 50. Peters JG: The motor unit in schizophrenic patients and their families. Biol Psychiatry 13:763-767, 1978 51. Crayton JW, Meltzer HY, Goode DJ: Motorneuron excitability in psychiatric patients. Biol Psychiatry 12:545-561, 1977 52. Goode DJ, Meltzer HY, Mazura TA: Hoffman reflex abnormalities in psychotic patients. Biol Psychiatry 14:95-l 10, 1979 53. Metz J, Goode DJ, Meltzer HY: Descriptive studies of H-reflex recovery curves in psychiatric patients. Psycho1 Med 10:541-548,198O 54. Meltzer HY (ed): Psychopharmacology: The Third Generation of Progress. New York, NY, Raven, 1987, pp 715-758 55. Brody JA, Chase TN, Gordon EK: Depressed monoamine catabolite levels in cerebrospinal fluid of patients with parkinsonism dementia of Guam. N Engl J Med 282:947-950,197O 56. Mendell JR, Chase TN, Engel WK: Amyotrophic lateral sclerosis: A study of central monoamine metabolism and therapeutic trial of levodopa. Arch Neural 25320-325, 1971 57. Ziegler MG, Brooks BR, Lake CR, et al: Norepinephrine and gamma-aminobutyric acid in amyotrophic lateral sclerosis. Neurology 30:98-101, 1980 58. Belendiuk K, Belendiuk GW, Freedman DX, et al: Neurotransmitter abnormalities in patients with motor neuron disease. Arch Neurol38:415-417,198l 59. Whitehouse PJ, Wamsley JK, Zarbin MA, et al: Amyotrophic lateral sclerosis: Alterations in neurotransmitter receptors. Ann Neurol 14:8-16, 1983 60. Tandan R, Bradley WG: Amyotrophic lateral sclerosis: Part 2. Etiopathogenesis. Ann Neurol 18:419-431, 1985 61. Metz J, Holcomb HH, Meltzer HY: Effect of chlorpromazine on a H-reflex recovery curves in normal subjects and schizophrenic patients. Psychopharmacology 78:342-345, 1982 62. Van Crevel H: A note on muscle atrophy of “central” origin. Psychiatr Neurol Neurochir 72~29-351969 63. McComas AJ, Sica REP, Campbell MJ: “Sick” motoneurones: A unifying concept of muscle disease. Lancet 1:321-325, 1971 64. Appel SH: A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and alzheimer disease. Ann Neural 10:499-505, 1981
and Amyotrophic
Lateral Sclerosis
Robert H. Howland Schizophrenia and amyotrophic lateral sclerosis (AL% are central nervous system KNS) disorders of unknown etiology. The association of these two disorders has been infrequently reported in the literature, but is not a rare occurrence. Various neuromuscular abnormalities involving the alpha-motor neuron have been described in some patients with schizophrenia. This report reviews the literature on schizophrenia, psychosis, and ALS and describes two additional cases of schizophrenia associated with ALS. The possibility that the neuromuscular dysfunction in schizophrenia may predispose to ALS and provide an explanation for the association of these two disorders is discussed. Additional research data are needed to test this hypothesis. 0 1990 by W. B. Saunders Company.
HE ETIOLOGY and pathophysiology of schizophrenia remain an enigma. However, although it has been characterized historically as a “functional” disorder, there is ever-increasing evidence that biochemical, neuroanatomical, and other organic factors are in fact involved. Many organic cerebral disorders have been found to be associated with schizophrenia-like psychoses, often indistinguishable clinically from functional schizophrenia.’ Amyotrophic lateral sclerosis (ALS), a motor system disorder, has been infrequently reported in the literature to be associated with schizophrenia or other psychoses. Although these disorders presumably affect different aspects of the central nervous system (CNS), each may manifest both motor and cognitive symptoms. Moreover, many similar factorsgenetic, viral, toxic-metabolic, and immunologic-have been implicated in their pathophysiology. This report will review the literature on schizophrenia, psychosis, and ALS, describe two cases of long-standing schizophrenia with the later onset of ALS, and discuss some of the implications of this association. ALS is a progressive degenerative syndrome of unknown etiology involving the upper and lower (alpha) motor neuron systems and is characterized clinically by muscle weakness, spasticity, hyperreflexia, fasciculations, muscle atrophy, dysarthria, and dysphagia. The specific clinical pattern of signs and symptoms may vary depending on the motor system, which is predominately affected. The terms progressive muscular atrophy (spinal alpha-motor neuron involvement), progressive bulbar palsy (brainstem alpha-motor neuron involvement), primary lateral sclerosis (corticospinal tract involvement), and progressive pseudobulbar palsy (corticobulbar tract involvement) have been used to describe them.* The term motor neuron disease (MND) has also been used generically to describe the spectrum of disorders affecting motor neurons. Ultimately, the symptoms progress to a final common state of total motor debilitation. Greater than 90% of cases are sporadic, although familial and juvenile cases are well described.3 The average annual incidence rate ranges from 0.4 to 1.8 per 100,000 population, the prevalence rate ranges from 4 to 6 per 100,000 population, and there is a slight male predominance.2 The average age
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From the Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine. Pittsburgh, PA. Address reprint requests to Robert H. Howland. M.D., Room 24, 381 I O’Hara St, Pittsburgh, PA 15213. Q 1990 by W.B. Saunders Company.
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of onset is 50 to 60 years, although the range is quite large, and death typically occurs within 5 years.4 Although ALS is classically described as a motor system disorder, there are a significant number of reports in the literature describing the occurrence of a variety of mental symptoms in association with ALS. The most commonly reported mental symptoms are cognitive changes and dementia. Dementia is reported to occur in up to 5% of cases of ALS’ and is well described in the parkinsonism-dementia-ALS complex of the Western Pacific5*6 and in a new entity, presenile dementia with MND.’ A syndrome characterized by ALS with a rapidly progressive dementia resembling Creutzfeldt-Jakob disease has been described,5,8y9although it is probably not transmissible.” A few cases of ALS with temporal lobe abnormalities and a dementia resembling Pick’s disease have also been described.11~12Finally, neuropsychological abnormalities without clinical evidence of dementia have been reported,‘3v’4 but these findings have not been supported by other studies.15 Emotional lability, characterized by pathological laughing and crying, frequently occurs in ALS, especially in cases with prominent bulbar or pseudobulbar symptoms.16-18Depression is felt to be commonly associated with ALS, although the incidence is unknown.2*‘6.19,20 Ho wever, other studies using personality inventories to assess patients with ALS have suggested a distinctive personality profile characterized by an unusually cheerful attitude,*l active mastery, and denial of depressive/ anxious feelings. **These findings were not supported by another study.23 In contrast to the cognitive impairment and affective symptoms described above, psychotic symptoms have been reported in association with ALS much less commonly. Ziegler16 reviewed some of the earliest reports in the European literature of psychosis in ALS and reported three cases of his own. In his review he cited a case reported by Fragnito (1907) that was “possibly affected with hallucinosis” (p. 630)i6 and a case reported by Pilcz (1908) of “a patient with persecutory ideas and hallucinations” (p. 63 1).16His own three cases included one in which the symptoms of psychosis preceded the onset of ALS by 3 years. Wechsler and DavisonI reviewed much of the same early literature on ALS and psychosis, but also cited the work of Van Bogaert (1925) who had reported on 10 of 31 cases of ALS with “characteristic psychotic disturbances” (p. 878).17 In addition, they described three cases of ALS that had postmortem neuropathological examinations; each patient had exhibited a psychosis that was felt to be due to the underlying neuropathology found in their study. They concluded that most cases of ALS are without psychotic manifestations, that those cases with psychosis are most likely to be coincidentally associated with functional psychotic disorders, and that in some cases of ALS the psychosis is related to an underlying cerebral pathological process that is a part of ALS. Androp described a case in which paranoid ideation was present for approximately 18 years before the diagnosis of ALS; the patient later developed auditory hallucinations and finally dementia before his death. Like Wechsler and Davison, Androp felt that the psychosis in this case was related to the underlying neuropathological changes that were noted at autopsy, although it is significant that the delusional thoughts preceded the onset of motor symptoms by a very long period of time. In a brief review of MND and schizophrenia-like psychoses, Davison and Bagleylg cited additional reports in the European literature by Westphal (1925),
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Recktenwald (1920), and Raithel (1941). Westphal (1925) described two patients with ALS who later developed paraphrenia phantastica and paranoid schizophrenia. Recktenwald (1920) reported a case of two sisters with progressive muscular atrophy who both later developed schizophrenia-like psychotic disorders. Raithel ( 194 1) described a case of schizophrenia that preceded the onset of ALS by some years. Meller25 reported a case of ALS with a paranoid type of psychosis and euphoria. Riley and Tirico26 described a case of ALS occurring in a patient who had hebephrenic schizophrenia for many years. Friedlander and Kesert27 presented a case of ALS with dementia and psychosis; the psychosis apparently was manifested by emotional lability and irrational and peculiar behavior. In the recent literature, Yvonneau2s reported an unusual case of paranoid schizophrenia complicated by a hypokalemic syndrome that was felt to be causally related to the later onset of ALS. Yase et a1.29described an interesting patient who had schizophrenic symptoms for 7 years before the onset of ALS. The postmortem neuropathological examination was remarkable for the presence of neurofibrillary tangles, although cognitive deficits were not noted in the clinical report. Finally, Burnstein3’ described an interesting family with an unusual constellation of neurological and psychiatric illnesses. One patient had a long-standing history of a schizophrenia-like illness and later developed ALS followed by dementia. An assessment of 36 extended family members over four generations demonstrated 13 persons with a variety of neurological and/or psychiatric illnesses, including ALS, dementia, Parkinson’s disease, brain tumor, epilepsy, schizophrenia-like and affective psychoses, and melancholia. This review appears to show that many patients with ALS will manifest psychotic symptoms, if present, shortly before or during the period of motor symptoms.‘6*‘9~25q27 In other patients, a psychotic disorder precedes the clinical syndrome by a longer Notable, also, is that the concept of psychosis as used by period of time. 16~19,24V26,29,30 some of the authors is not well defined. In many cases the reported psychotic symptoms may be indistinguishable from a dementia, delirium, or other organic psychosis directly related to the CNS pathology of ALS; other cases clearly demonstrate what may be regarded as true functional psychoses in association with the later development of ALS. Two cases of long-standing schizophrenia with the late onset of ALS will now be presented and some implications of this association will be discussed. CASE REPORTS Case 1 Mr. A was a 39-year-old white man with a 14-year history of chronic paranoid schizophrenia when he initially presented for a neurological evaluation in 1986 with the complaint of muscle stiffness, difficulty swallowing, and difficulty talking of at least 4 months’ duration. He stated that he had experienced a sudden weakness in his left side approximately 1 month before his presentation, but did not seek medical attention. He felt that it had improved since that time. He had no other significant medical history, including drug or alcohol use. During the recent past he apparently had more frequent relapses and rehospitalizations with poor functioning overall. Mr. A’s neurological evaluation (including a computed tomography [CT] scan, electromyogram [EMG] study, and muscle biopsy) was consistent with a right hemisphere cerebrovascular accident and ALS. His subsequent course was marked by a rapid deterioration in his functioning and health, although he suffered no apparent recurrence of his psychosis. He died 10 months later of an aspiration pneumonia. An autopsy study was remarkable for brain
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atrophy, rarefaction of the corticospinal tracts within the spinal cord, and small hyperchromatic motor neurons, consistent with the clinical diagnosis.
Case 2 Mr. B was a 50-year-old white man with a 30-year history of chronic paranoid schizophrenia when he initially presented for a neurological evaluation in 1986 with a complaint of muscle “twitches” in his arms and legs and difficulty walking for 4 months. He had no significant medical history, including drug or alcohol use. His neurological evaluation (including an magnetic resonance image [MRI] scan and EMG study) was consistent with ALS. Mr. B’s neurological illness progressed rapidly and he died 1 year after his diagnosis. An autopsy was not performed.
DISCUSSION
These two cases of ALS were characterized by an associated schizophrenia existing 14 years and 30 years, respectively, before the development of the MND. There were no other known physical conditions to account for the psychotic and neuromuscular symptoms; although the first patient also had suffered a recent cerebrovascular accident, there was no evidence relating it to either the psychosis or the neuromuscular abnormalities. Whenever two CNS disorders are found to exist in the same patient, it would be of clinical and scientific interest to know whether there is causal relationship between the two conditions, if they have a common etiology, or if they merely coexist by a chance association. The implications of such an association are important to consider, not only because they may provide valuable insights into the etiology and pathophysiology of the coexistent disorders or related conditions, but also because additional aspects of the clinical picture and natural history of the disorders may be identified. In those cases of ALS reviewed above, in which the psychosis occurs shortly before or during the course of the neuromuscular symptoms, it would be reasonable to conclude that the psychosis is organic in nature and related to the underlying pathological CNS process of ALS.‘6~‘g~25~27 In support of this are those cases in which the neuropathological findings demonstrate diffuse CNS changes extending beyond the classically defined abnormalities of the motor nuclei and corticospinal tracts.‘7*24V2g Also, extensive CNS abnormalities have been well described in other neuropathologmaking it quite possible that impairment of other CNS ical studies of ALS,5V31V32 functioning in ALS may occur in addition to the motor dysfunction. When a presumed functional psychotic disorder, such as schizophrenia, exists in a patient who later develops ALS (often years apart, since the average age of onset of schizophrenia is much earlier than that of ALS), it would be difficult to demonstrate that a causal relationship exists or that there is a common etiology for the two disorders. This is especially so when the etiology and pathophysiology are unknown and biological markers do not exist for these disorders. To determine a possible linkage would then depend on the demonstration that ALS occurred more frequently in a population with schizophrenia than in a normal control population or, conversely, that a history of schizophrenia is more frequent in a population with ALS than in a normal control population. Baldwin33 has described the various methodological issues and problems encountered in using population studies to assess the relationship between physical disease and schizophrenia. When one or both disorders have a relatively low incidence and prevalence, as with ALS, a large number of patienrs, and a thorough ascertainment of cases, would be needed to show a greater than expected chance of association. In addition, the excess mortality and
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premature death found in schizophrenia34 may effectively reduce the number of cases of schizophrenia that reach the ages of highest risk for the development of ALS, unless it can be demonstrated that ALS itself accounts for some of the excess mortality. To my knowledge, no epidemiological studies have been conducted that have specifically examined the incidence and prevalence of ALS in schizophrenia or systematically assessed the psychiatric history in ALS. Although various neurological signs and symptoms have been well described in a large percentage of persons with schizophrenia, they are generally regarded as nonspecific. Very little information is available in the literature that describes specific neurological syndromes, such as ALS, or examines the progression of the neurological abnormalities in schizophrenia over time.35 Exceptions to this are the well-known problems of tardive dyskinesia and other extrapyramidal syndromes. Many studies have examined the mortality rate and cause of death in schizophrenia, focusing primarily on such categories of morbidity as infectious disease, cancer, cardiovascular disorders, accidents, and suicide. Those studies that also include a category of conditions affecting the nervous system generally have not specified particular neurological disorders or report only such major conditions as brain neoplasms and cerebrovascular disease. As a result, there is little data to address the issue of the incidence and prevalence of ALS in schizophrenia. However, Mettler and Crandel136 were specifically interested in the incidence of neurological disorders in an institutionalized psychiatric population. In their meticulous assessment of 5,704 patients they found five cases of progressive pseudobulbar palsy and at least one case each of ALS and bulbar palsy (the authors did not specify the exact numbers). These seven cases of MND would suggest an estimated prevalence of MND in this institution of approximately 120 per 100,000 population, a rate considerably higher than most estimates in the general population. These results cannot necessarily be generalized to schizophrenia, because the study population consisted of both functional and organic disorders and the specific diagnoses of the patients with MND are not reported. Nevertheless, these findings suggest that if a careful assessment is done, MND may be present more often than expected in a chronically ill psychiatric population. Additional study in other psychiatric populations is warranted. An alternate method of studying the association between schizophrenia and ALS is to assess the psychiatric history of a group with ALS. As with schizophrenia, a large number of epidemiological studies of ALS have been performed and many have included data on various associated physical conditions. However, few of these studies report on the psychiatric history of their subjects. Jokelainen37 investigated 255 cases of ALS in Finland and found that 14 (5%) had a history of “psychiatric disorder or mental retardation.” This finding is difficult to interpret since specific diagnoses were not reported and there was no control population to determine whether this percentage was significantly different than expected. In a case-control study, Kurtzke and Beebe38 found 51 cases of “mental disorders” (the diagnoses were unspecified) in a cohort of 504 veterans with ALS and 45 cases in a control group of 504 veterans without ALS. The difference was not significant. However, as designed, this study could not adequately address the issue of the psychiatric history in ALS for two reasons. First, the subjects were selected for the presence or absence of ALS and incomplete military service record abstracts were examined retrospec-
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tively for any psychiatric disorders noted only at the time of induction into military service or during the period of their military service. Thus, many psychiatric conditions were likely to be missed. Second, persons who would otherwise have been eligible for induction into the service, and might later develop ALS, may have been rejected due to a preexisting mental disorder, especially a disorder of early onset such as schizophrenia. Therefore, assuming that schizophrenia would be only one of multiple antecedents of ALS, this particular study population would be biased against including cases associated with schizophrenia, making it difficult to determine if schizophrenia is indeed associated with ALS. Finally, Forsgren et al.3g reported only one subject with schizophrenia out of 128 cases of ALS in northern Sweden, but their study was not intended to look for disorders associated with ALS. As can be seen from the available epidemiological data, no firm conclusions can be made as to the significance of the psychiatric history in ALS. Given the paucity of information that exists in the epidemiological literature of both schizophrenia and ALS that pertains to their possible association, the issue cannot be definitively resolved. However, other clinical and experimental evidence exists that may be relevant to a consideration of the coexistence of these two disorders. As discussed above, schizophrenia is often associated with a variety of neurological abnormalities, generally with a prevalence greater than that of other psychiatric disorders and nonpsychiatric controls. 35These abnormalities would be of particular relevance in this regard if they included abnormalities of the neuromuscular system as well. In fact, various abnormalities of the neuromuscular system have been described in some psychotic disorders, although this has been studied most extensively in schizophrenia. 40-43Serum creatine phosphokinase (CPK), derived from skeletal muscle, has been shown to be elevated in many patients during acute episodes of psychosis. 40*44,45 CPK may also be relatively elevated during nonacute phases of the illness and in first-degree relatives of schizophrenics.40*42 Skeletal muscle biopsy specimens from some patients with schizophrenia have shown a variety of morphological abnormalities,43346 which have been noted in some of their firstdegree relatives also. 40,44Increased branching of subterminal motor neurons (the most distal region of the alpha-motor neuron proximal to the motor endplate) has been described in patients43 and first-degree relatives,40 suggesting a process of motor neuron degeneration and regeneration.44347*48Electrophysiological studies have demonstrated abnormalities of the alpha-motor neuron and motor unit that are Some of these abnormalities consistent with denervation and reinnervation. 41946V4g also have been found in first-degree relatives. So Finally, abnormalities of the Hoffman reflex (H-reflex) have been described.40V41351-53 The H-reflex is an electrically evoked monosynaptic spinal cord reflex that provides an index of alpha-motor neuron excitability. Therefore, the abnormalities of the H-reflex in these studies are an indication of altered alpha-motor neuron excitability in schizophrenia. These abnormalities are felt to be most consistent with a neurogenic, rather than They have been found to persist during the course of the myopathic, process. 44,48V4g illness, irrespective of such factors as age, duration of illness, number of psychotic episodes, frequency of hospitalization, medication use, intercurrent physical illness, although long-term follow-up has not been reported. There is or drug abuse, 40*4’s46 some evidence that the H-reflex may differ in acute and chronic patients, suggesting
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that the neuromuscular abnormality may be related to the chronicity of the illness. 40,41351-53 The cause of these neuromuscular abnormalities in schizophrenia is unknown, although it has been postulated that they may result from some type of endogenous substance toxic to alpha-motor neurons,40’48some intrinsic alpha-motor neuron pathology,40 a supraspinal CNS derangement with an altered neurotrophic influence on the alpha-motor neuron,48,51a generalized cell membrane or neuronal defect,46 or central neurotransmitter abnormalities. 46*51-53 In addition, that these findings exist in some first-degree relatives suggests a genetic diathesis. The clinical significance of these abnormalities in schizophrenia has not been systematically studied and is unknown. It has been suggested that they may contribute to the vulnerability to psychosis,42 the neuromotor dysfunction found in schizophrenia (such as abnormal eye-tracking),40*44 and the disordered motor development and function seen in children of schizophrenics.42*46 However, these neuromuscular abnormalities also strongly imply an ill-defined dysfunction of the alpha-motor neuron in schizophrenia. Furthermore, all have been described in ALS as we11.2’4It is conceivable that the association of schizophrenia and ALS as described in these case reports and in the literature may not be coincidental and may be understood on the basis of these neuromuscular abnormalities. This hypothesis suggests that the neuromuscular dysfunction in schizophrenia represents an abnormality of the alpha-motor neuron and that this abnormality may predispose at least some patients with schizophrenia to the later development of ALS, since the diseased alpha-motor neuron is a sine qua non of ALS. How this abnormality arises is open to speculation. Genetic, toxic-metabolic, and immunologic factors, implicated in both disorders, remain unproven. One possibility of particular interest is the role of central neurotransmitters. Various central neurotransmitter abnormalities are noted in schizophrenias4 and have also been described in ALS.55-58 In addition, neurotransmitter receptors exist in the spinal cord, including the anterior horn, and alterations in these have been described in ALS.49sgX60 Altered central neurotransmission, such as increased dopamine, may adversely affect the alpha-motor neuron,5’-53*6’causing injury to it directly or rendering it susceptible to injury from another insult. In this scenario, abnormal neurotransmitter levels in some schizophrenics may be a potential mechanism of alpha-motor neuron injury leading to ALS. The possibility that injury to the peripheral nervous system can occur by such an altered central neurotrophic effect has been described elsewhere.62*63 Moreover, altered neurotrophism has been suggested as a unifying concept to explain the neurodegeneration in Alzheimer’s disease, Parkinson’s disease, and ALS64 and would be consistent with this hypothesis. Ultimately, whether the coexistence of these two disorders is the result of a common etiological factor or is due to some other factor associated with schizophrenia that renders them susceptible to ALS cannot be determined with the available data. Also, whether the neuromuscular abnormality in schizophrenia is a primary or secondary phenomenon cannot be definitively resolved. However, this type of abnormality does suggest a potential biological link between schizophrenia and ALS, a disorder affecting the motor neuron. Since the neuromuscular abnormalities are not present in all schizophrenics, and the severity may vary, it is not likely that ALS would be a common clinical sequela of schizophrenia. Further investigation of
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the association of schizophrenia and ALS would require larger numbers of patients, comprehensive neurological evaluations in schizophrenia with particular attention to neuromuscular disorders (especially in older chronically ill schizophrenics), long-term prospective follow-up of schizophrenics with and without the neuromuscular abnormalities described above, additional laboratory studies to better characterize these findings, and postmortem neuropathological studies of the spinal cord in schizophrenia. The benefit of further investigations in this area would be to acquire additional knowledge of the systemic abnormalities and novel clinical features of the schizophrenic syndrome, better characterize the natural history of schizophrenia, and develop new insights into the etiology and pathophysiology of ALS and other neuromuscular disorders. ACKNOWLEDGMENT The author would like to thank Karen Neal for her work in the preparation of the manuscript.
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