Neurology_Adams

Neurology_Adams. is of early diaphragmatic weakness; such cases come to attention because of respiratory failure. A symmetrical proximal limb or shoulder-girdle amyotrophy with onset at an early age is also known and simulates muscular dystrophy (Wohlfart-Kugelberg-Welander disease, discussed later in this chapter). On several occasions we have observed a pattern involving the arm and leg on the same side, first with spasticity and then with some degree of amyotrophy; this has been called the hemiplegic or Mills variant. However, this clinical pattern more often turns out to be a result of multiple sclerosis of compression of the spinal cord from laterally, as occurs with a neurofibroma.


Neurology_Adams

Neurology_Adams. The first and dominant manifestations of motor neuron disease may be a spastic weakness of the legs, in which case a diagnosis of primary lateral sclerosis is tentatively made (discussed further on); only after a year or two, do the hand and arm muscles weaken, waste, and fasciculate, making it obvious that both upper and lower motor neurons are diseased. Early on, a spastic bulbar palsy with dysarthria and dysphagia, hyperactive jaw jerk and facial reflexes, but without muscle atrophy, may be the initial phase of disease.


Neurology_Adams

Neurology_Adams. As the disease advances, very mild distal sensory loss may be observed in the feet without explanation, but, if the sensory loss is a definite and early feature, the diagnosis must remain in doubt. Between 5 and 20 percent of cases of ALS are observed in conjunction with a frontotemporal dementia although careful testing is said to expose a larger proportion of executive or other neuropsychiatric dysfunction; less commonly there is an association with a Parkinson syndrome.


Neurology_Adams

Neurology_Adams. Laboratory features of motor neuron disease Investigation provides useful confirmatory evidence even in the typical clinical syndrome. The EMG, as expected, displays widespread fibrillations (evidence of active denervation) and fasciculations and enlarged motor units (denoting reinnervation), and motor nerve conduction studies reveal only slight slowing, without focal motor conduction block. If the atrophic paresis is restricted to an arm or hand, raising the question of cervical spondylosis, evidence of denervation in many widely separated somatic segments favors the diagnosis of ALS. In questionable cases, it is good practice to insist that denervation be demonstrated in at least 3 limbs before concluding that the process is ALS. (The currently favored “El-Escorial” criteria that are used for the purposes of clinical research mandate that this finding be present.) Widespread denervation of the paraspinal muscles and of the genioglossus or facial muscles is also strongly suggestive


Neurology_Adams

Neurology_Adams. for the purposes of clinical research mandate that this finding be present.) Widespread denervation of the paraspinal muscles and of the genioglossus or facial muscles is also strongly suggestive of the disease but electromyographic testing of these muscles demands considerable experience and is uncomfortable for patients. A muscle biopsy is sometimes helpful in corroborating neurogenic denervation. Sensory nerve action potentials should be normal but may show slightly low amplitude; tests of motor nerve conduction have a normal velocity, but the amplitudes become progressively lower as the disease progresses—in the earliest stages, they too may be normal. When in a typical case the amplitudes of sensory nerve action potentials are reduced, there is usually an underlying entrapment neuropathy, diabetes, or other late-life neuropathy. Sensory evoked potentials are mildly abnormal in a proportion of patients, but the explanation for this finding is unclear. (Sensory complaints and


Neurology_Adams

Neurology_Adams. diabetes, or other late-life neuropathy. Sensory evoked potentials are mildly abnormal in a proportion of patients, but the explanation for this finding is unclear. (Sensory complaints and minimal sensory loss have been commented on above.)


Neurology_Adams

Neurology_Adams. The CSF protein is usually normal or marginally elevated. Serum creatine kinase is moderately elevated in patients with rapidly progressive atrophy and weakness, but it is just as often normal. Motor evoked potentials elicited from the cortex are also prolonged in patients with prominent corticospinal signs. In this group, the MRI may show slight atrophy of the motor cortices and wallerian degeneration of the motor tracts (Fig. 38-10). These changes may be diagnostically useful and appear as increased FLAIR and T2 signal intensity in the posterior limb of the internal capsule, descending motor tracts of the brainstem, and spinal cord, all of which are subtle and may be missed. All these laboratory findings, particularly the degeneration of the lateral columns of the cord and changes in the internal capsules, pertain also to primary lateral sclerosis with the notable exception of EMG findings of denervation and of elevations of creatine kinase (CK).


Neurology_Adams

Neurology_Adams. Pathology The principal finding in ALS is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem. The anterior roots are thin, and there is a disproportionate loss of large myelinated fibers in motor nerves (Bradley et al). The muscles show typical denervation atrophy of different ages. Large alpha motor neurons tend to be affected before small ones. In addition to neuronal loss, there is evidence of slight gliosis and proliferation of microglia cells. Many of the surviving nerve cells are small, shrunken, and filled with lipofuscin. It is not uncommon to detect ubiquitin inclusions in threads, skeins, or dense aggregates within the affected neurons by special stains. Occasionally, there is another ill-defined cytoplasmic inclusion that is present in neurons and glia. Most studies indicate that these are made up of TDP-43 and ubiquitin as discussed in the alter section on “Pathogenesis.” Cases ostensibly associated with repeated trauma


Neurology_Adams

Neurology_Adams. present in neurons and glia. Most studies indicate that these are made up of TDP-43 and ubiquitin as discussed in the alter section on “Pathogenesis.” Cases ostensibly associated with repeated trauma (see earlier) show an accumulation of tau in anterior horn cells, similar to the findings in the cerebral cortex that characterize chronic traumatic encephalopathy. According to some reports, swelling of the proximal axon is an early finding, presumably antedating visible changes in the cell body itself. There is an understandable depletion of muscarinic, cholinergic, glycinergic, and benzodiazepine receptors in regions of the spinal cord where motor neurons had disappeared.


Neurology_Adams

Neurology_Adams. The corticospinal tract degeneration is most evident in the lower parts of the spinal cord, but it can be traced up through the brainstem to the posterior limb of the internal capsule and corona radiata by means of fat stains, which show the macrophages that accumulate in response to chronic myelin degeneration. There is a loss of Betz cells in the motor cortex; this is manifest as a slight frontal lobe atrophy on the MRI, but it is not a prominent finding in most cases of ALS (Kiernan and Hudson). Other fibers in the ventral and lateral funiculi are depleted, imparting a characteristic pallor in myelin stains. Some pathologists have interpreted this as evidence of involvement of nonmotor neurons and hence object to the term motor system disease. However, this condition of more diffuse pallor may be a result of a loss of collaterals of motor neurons that contribute to the lamina propria. One observes the same effect in long-standing poliomyelitis. In cases of familial ALS resulting


Neurology_Adams

Neurology_Adams. pallor may be a result of a loss of collaterals of motor neurons that contribute to the lamina propria. One observes the same effect in long-standing poliomyelitis. In cases of familial ALS resulting from mutations in the SOD1 gene, the nonmotor systems seem to be more affected (Cudkowicz et al).


Neurology_Adams

Neurology_Adams. Neuropathologic studies of cases of ALS with dementia have been increasingly reported and studied histopathologically. In addition to the usual loss of motor neurons, these cases have shown an extensive neuronal loss, gliosis, and vacuolation involving the frontal premotor area, particularly the superior frontal gyri and the inferolateral cortex of the temporal lobes. The neurons in typical cases contain TDP-43 (ubiquitin). The histologic changes of Alzheimer or Pick disease have not been seen but neurofibrillary degeneration (tau) has been observed, but is inconsequential in comparison to that seen in the Guamanian Parkinson-dementia-ALS complex (Finlayson et al). This purely lower motor neuron syndrome is more common in men than in women, reportedly in a ratio of 4:1. It probably encompasses several diseases of the lower motor neuron, but most of which are aligned with ALS.


Neurology_Adams

Neurology_Adams. These purely lower motor neuron amyotrophies tend to progress at a slower pace than the usual case of ALS, some patients surviving for 15 years or longer. Chio and colleagues (1985), who analyzed the factors affecting life expectancy in 155 patients with progressive muscular atrophy (PMA), found that younger patients had a more benign course: The 5-year survival was 72 percent in patients with an onset before age 50 years and 40 percent in patients with onset after age 50 years. Some of the most chronic varieties of PMA are familial. It has been revealed that the original report of a familial variety of this illness by William Osler is in a family now known to have had a mutation in the SOD1 gene, as discussed earlier. In about half the patients, the illness takes the form of a symmetrical (sometimes asymmetrical) wasting of intrinsic hand muscles, slowly advancing to the more proximal parts of the arms; less often, the legs and thighs are the sites of the initial atrophic weakness;


Neurology_Adams

Neurology_Adams. (sometimes asymmetrical) wasting of intrinsic hand muscles, slowly advancing to the more proximal parts of the arms; less often, the legs and thighs are the sites of the initial atrophic weakness; or the proximal parts of the limbs are affected before the distal ones. Fascicular twitchings and cramping are variably present. Otherwise, they differ from ALS only in that the tendon reflexes are diminished or absent, and signs of corticospinal tract disease cannot be detected. Nonetheless, many cases of ostensible PMA are found to have indications of corticospinal tract degeneration at autopsy (Ince et al).


Neurology_Adams

Neurology_Adams. The main disease to be distinguished from PMA is an immune-mediated motor neuropathy that occurs with or without multifocal block of electrical conduction (see Chap. 43), and various muscle diseases that produce a similar pattern of weakness, notably, inclusion body myopathy and polymyositis. A more extensive differential diagnosis of PMA is discussed further on.


Neurology_Adams

Neurology_Adams. Here reference is made to a condition in which the first and dominant symptoms relate to weakness and laxity of muscles innervated by the motor nuclei of the lower brainstem, that is muscles of the jaw, face, tongue, pharynx, and larynx. This weakness gives rise to an early defect in articulation, in which there is difficulty in the pronunciation of lingual (r, n, l), labial (b, m, p, f), dental (d, t), and palatal (k, g) consonants. As the condition worsens, syllables lose their clarity and run together, until, finally, the patient’s speech becomes unintelligible. In other patients, slurring is a result of spasticity of the tongue, pharyngeal, and laryngeal muscles; the speech sounds as if the patient were eating food that is too hot. Usually the voice is modified by a combination of atrophic and spastic weakness. Defective modulation with variable degrees of rasping and nasality is another characteristic. The pharyngeal reflex is lost, and the palate and vocal cords move imperfectly


Neurology_Adams

Neurology_Adams. and spastic weakness. Defective modulation with variable degrees of rasping and nasality is another characteristic. The pharyngeal reflex is lost, and the palate and vocal cords move imperfectly or not at all during attempted phonation. Mastication and deglutition become impaired; the bolus of food cannot be manipulated and may lodge between the cheek and teeth and the pharyngeal muscles do not force it properly into the esophagus. Liquids and small particles of food find their way into the trachea or nose. The facial muscles, particularly of the lower face, weaken and sag. Fasciculations and focal loss of tissue of the tongue are usually early manifestations; eventually the tongue becomes shriveled and lies useless on the floor of the mouth. The chin may also quiver from fascicular twitchings, but the diagnosis should not be made on the basis of fasciculations alone, in the absence of weakness and atrophy.


Neurology_Adams

Neurology_Adams. The jaw jerk may be present or exaggerated at a time when the muscles of mastication are markedly weak. In fact, spasticity of the jaw muscles may be so pronounced that the slightest tap on the chin will evoke clonus and blinking; rarely, attempts to open the mouth elicit a “bulldog” reflex (jaw snaps shut involuntarily). Spastic weakness of the oropharyngeal muscles may be the initial manifestation of bulbar palsy and may at times surpass signs of atrophic weakness; pseudobulbar signs (pathologic laughing and crying) may reach extreme degrees. This is the only common clinical situation in which spastic and atrophic bulbar palsy coexist. Strangely, the ocular muscles always escape.


Neurology_Adams

Neurology_Adams. As with other forms of motor system disease, the course of bulbar palsy is inexorably progressive. Eventually the weakness spreads to the respiratory muscles and deglutition fails entirely; the patient dies of inanition and aspiration pneumonia, usually within 2 to 3 years of onset. Approximately 25 percent of cases of motor system disease begin with bulbar symptoms, but rarely, if ever, does the sporadic form of progressive bulbar palsy run its course as an independent syndrome (pure heredofamilial forms of progressive bulbar palsy in the adult are known, for example, Kennedy disease, discussed further on). In general, the earlier the onset of the bulbar involvement, the shorter the course of the disease.


Neurology_Adams

Neurology_Adams. This entity can be considered a special form of motor neuron disease, although many authorities classify it as a unique degenerative process. Many patients in whom the signs of corticospinal tract degeneration suggest the presence of ALS will develop indications of lower motor neuron disease within 1 year, usually earlier. Approximately 20 percent, however, have a slowly progressive corticospinal tract disorder that begins with a pure spastic paraparesis; later, the arms and oropharyngeal muscles become involved and the disease remains one solely of the upper neurons. These cases have distinctive neuropathologic features and are designated as primary lateral sclerosis (PLS), a term originally suggested by Erb in 1875. A historical review of the subject appears in the article by Pringle and colleagues.


Neurology_Adams

Neurology_Adams. The typical case begins insidiously in the fifth or sixth decade with a stiffness in one leg, then in the other; there is a slowing of gait, with spasticity predominating over weakness as the years go on. Walking is still possible with the help of a cane for many years after the onset, but eventually this condition acquires the characteristic features of a severe spastic paraparesis. Over the years, finger movements become slower, the arms become spastic, and, if the illness persists for decades, speech takes on a pseudobulbar lilt. There are no sensory symptoms or signs. The legs are often found to be surprisingly strong, the difficulty in locomotion being attributable to rigid spasticity. About half the patients eventually acquire spasticity of the bladder. Pringle and associates suggest that a diagnostic criterion of the disease is progression for 3 years without evidence of lower motor neuron dysfunction.


Neurology_Adams

Neurology_Adams. Pathologic studies in a limited number of cases have disclosed a relatively stereotyped pattern of reduced numbers of Betz cells in the frontal and prefrontal motor cortex, degeneration of the corticospinal tracts, and preservation of motor neurons in the spinal cord and brainstem (Beal and Richardson; Fisher; Pringle et al). The corticospinal tract lesions are identical to those in typical ALS. Whether some of these cases are examples of late-onset familial spastic paraplegia (see earlier) has not been extensively explored with molecular techniques.


Neurology_Adams

Neurology_Adams. Some patients who have only restricted bilateral signs of upper motor neuron disease prove to have multiple sclerosis, a slow compression of the spinal cord by spondylosis or meningioma, spinal dural arteriovenous fistula, or the myelopathic form of adrenoleukodystrophy (affected males or female carriers). In a few cases, tropical spastic paraplegia, HIV myelopathy, copper deficiency myelopathy, or a familial type of spastic paraplegia (described further on) will be uncovered. Exceptionally, progressive spastic paraparesis has been linked to an adult onset of phenylketonuria or other aminoacidopathies to vitamin B12 deficiency or to the fragile X premutation syndrome. Diagnosis of ALS


Neurology_Adams

Neurology_Adams. Diagnosis of ALS The early clinical picture of motor system disease is closely simulated by a centrally placed cervical spondylotic bar or ruptured cervical disc, but with these conditions there is usually pain in the neck and shoulders, limitation of neck movements, and sensory changes, and the lower motor neuron changes are restricted to 1 or 2 spinal segments. The EMG is helpful, if not decisive, in differentiating these disorders. A mild hemiparesis or monoparesis because of multiple sclerosis may be, for a time, difficult to distinguish from early ALS and primary lateral sclerosis. Progressive spinal muscular atrophy may be differentiated from peroneal muscular atrophy (Charcot-Marie-Tooth neuropathy) by the lack of family history, the complete lack of sensory change, and different EMG patterns, as described in Chap. 43. Motor system disease beginning in the proximal limb muscles may be misdiagnosed as an inflammatory myopathy or a limb-girdle type of muscular dystrophy.


Neurology_Adams

Neurology_Adams. Chap. 43. Motor system disease beginning in the proximal limb muscles may be misdiagnosed as an inflammatory myopathy or a limb-girdle type of muscular dystrophy. The main considerations in relation to progressive bulbar palsy are myasthenia gravis and, less often, inflammatory myopathy, muscular dystrophy, and especially the inherited (Kennedy et al) type of bulbospinal atrophy, which is discussed further on. The spastic form of bulbar palsy may suggest the pseudobulbar palsy of lacunar disease and can be a prominent part of the progressive supranuclear palsy described earlier in the chapter. A crural form of PMA may be confused with diabetic polyradiculopathy or polymyositis.


Neurology_Adams

Neurology_Adams. A major consideration is the differentiation of PMA from a chronic motor polyneuropathy, particularly the form that displays multifocal conduction block. Extensive nerve conduction studies and EMG examinations are necessary to distinguish the two; these neuropathic processes are discussed with the peripheral neuropathies in Chap. 43. The presence of an IgM monoclonal paraproteinemia or of specific antibodies directed against the GM1 ganglioside are usually indicative of the immune motor neuropathy, but in half of the cases these laboratory tests are negative. There is also a rare form of subacute poliomyelitis (possibly viral) in patients with lymphoma or carcinoma; it leads to an amyotrophy that progresses to death over a period of several months. Chapter 30 discusses this paraneoplastic variety of motor system disease in greater detail.


Neurology_Adams

Neurology_Adams. Because it may produce a motor-predominant radiculopathy, Lyme infection is sometimes considered in the differential diagnosis of ALS. Some clinics screen for Lyme antibodies using both an enzyme-linked immunosorbent assay (ELISA) and the more sensitive and specific Western immunoblot, but we have never detected such a case and doubt there is much similarity. Infrequently, we have seen myelopathic motor findings and motor radiculopathy with vitamin B12 deficiency (or copper deficiency), and there are exceptional reports of myeloradiculopathy with lead poisoning; we sometimes include tests for these conditions. Another entity that may simulate ALS is inclusion body myositis (IBM), an atypical myopathy that begins asymmetrically and involves distal muscles, usually without much elevation of serum CPK levels. In a recent series of 70 patients with this condition, 13 percent were initially diagnosed as having ALS (Dabby et al). Features distinguishing the IBM cases included normal


Neurology_Adams

Neurology_Adams. of serum CPK levels. In a recent series of 70 patients with this condition, 13 percent were initially diagnosed as having ALS (Dabby et al). Features distinguishing the IBM cases included normal corticospinal function, preservation of deep tendon reflexes in weak muscles, and finger flexor weakness. One concludes from this series that a detailed, quantitative EMG and possibly a muscle biopsy are indicated in cases that display predominantly lower motor features. Fully developed ALS is difficult to confuse with these conditions. Acid maltase deficiency may also simulate ALS in causing fatigability and early respiratory failure.


Neurology_Adams

Neurology_Adams. Over the years, the authors have encountered young men with localized and asymmetrical amyotrophy of the forearm that became arrested and did not advance over a decade or two, typical of Hirayama disease. Reports of such a partial cervical spinal amyotrophy have appeared (Hirayama et al; Moreno Martinez et al). In the type described by Hirayama and associates, young men are affected with progressive and asymmetrical amyotrophy of the forearm and hand that has been traced to ligamentous hypertrophy and buckling in the ventral spinal canal. This causes a compression of the cervical spinal cord gray matter, presumably by a chronic ischemic effect as discussed in detail in Chap. 42. In a familial variety of pure restricted amyotrophy, only the vocal cords became paralyzed over a period of years in adult life; only later were the hands affected.


Neurology_Adams

Neurology_Adams. Some patients who have recovered from paralytic poliomyelitis may develop progressive muscular weakness 30 or 40 years later; the nature of this relationship is obscure. We favor the explanation that atrophy of anterior horn cells with aging brings to light a critically depleted motor neuron population (see further on). It appears to progress little if at all. An observation of interest is the finding of a form of progressive spinal muscular atrophy in patients with GM2 gangliosidosis, the storage disease that presents in infancy as Tay-Sachs disease (Kolodny and Raghavan). The onset is in late adolescence and early adult life and the atrophic paralysis is progressive, so that this condition is often mistaken for Wohlfart-Kugelberg-Welander disease or ALS. A number of cases of this type were discovered in


Neurology_Adams

Neurology_Adams. Ashkenazi Jews by the use of lysosomal enzyme analysis and currently, by genetic testing. The rare and incompletely characterized entity of polyglucosan disease, discussed in other sections of the book, has simulated ALS. The differential diagnosis of the purely spastic state of primary lateral sclerosis is broad and has been listed earlier. An estimate of the frequency of all the aforementioned alternative diagnoses may be appreciated from a study of cases by Visser and colleagues that were initially presumed to be PMA but turned out to represent another process. In 17 of 89 patients the diagnosis proved to be anti-GM1 motor conduction block, chronic inflammatory demyelinating polyneuropathy, and various myopathies. This notwithstanding, ALS or the more discrete forms of motor system disease rarely offer any difficulty in diagnosis.


Neurology_Adams

Neurology_Adams. Insight into the sporadic form of the disease has been afforded by analyses of the approximately 10 percent of ALS cases that are familial and those caused by identifiable sporadic mutations. These genetic and molecular influences are summarized by Brown and Al-Chalabi. They are inherited mainly in an autosomal dominant pattern (Table 38-6). Of these forms with a known family history, approximately 40 percent are associated with a hexanucleotide expansion in the C9orf 72 gene. Provocatively, 5 to 10 percent of presumably sporadic cases also have mutations in the gene, however, these numbers are derived from studies that excluded nonmotor manifestations in family members, namely frontotemporal dementia; therefore, the number of sporadic cases of ALS explained by the mutation is probably less than the 5 to 10 percent given above. The mechanism of motor neuron death that results from this mutation is not known but may be associated with mishandling of RNA-binding proteins.


Neurology_Adams

Neurology_Adams. Of similar interest are the TARDBP and FUS genes that each has an association with approximately 5 percent of familial cases and 2 percent of sporadic ones. They may damage motor neurons through mechanisms of altered protein degradation. The SOD1 mutation, the first to be found in familial ALS, codes for the cytosolic enzyme Cu-Zn superoxide dismutase (SOD1; Rosen et al); it has also been implicated in a small proportion of sporadic cases. There are yet other mutations in this group that have associations, not necessarily causal, with small numbers of both sporadic and inherited cases (Table 38-7). As already alluded to, all 3 of the aforementioned genes have also been implicated in degenerative frontotemporal dementia and in the combination of this dementia with ALS.


Neurology_Adams

Neurology_Adams. A rare and recessively inherited childhood form of motor neuron disease (affecting corticospinal more than spinal motor neurons) has been attributed to mutations in a gene whose protein (alsin) is a component of the neuronal cell-signaling pathways. Yet another rare childhood-onset form of disease arises from mutations in the senataxin gene, a DNA helicase that probably assists in chromatin folding and unfolding. (It is of interest that a recessively inherited mutation in the same gene transmits a form of ataxia with oculomotor disorder.) In several families, a mutation has been detected in a protein that is involved in the transport of vesicles in neurons. Table 38-6 summarizes some of the known genetic forms of motor neuron disease.


Neurology_Adams

Neurology_Adams. Trauma, particularly traction injury of an arm, but also repetitive head and spine injury has been reported occasionally as an antecedent event in patients with ALS, but a causative relationship has not been established. Younger and coworkers have found a higher incidence of paraproteinemia in patients with motor system disease than can be accounted for by chance. Many other examples of disordered immune function have been described but a coherent explanation of ALS as an autoimmune disease has not emerged. It has never been proved that intoxication with heavy metals (lead, mercury, aluminum) can cause motor system disease, although there are reports of concurrent myelopathic and radicular motor signs in patients with lead intoxication. There is little evidence that ALS represent a reactivation of a virus or the presence of some other infectious agent. The progressive weakness that occurs some 30 to 40 years after recovery from polio should not be confused with PMA, as already


Neurology_Adams

Neurology_Adams. reactivation of a virus or the presence of some other infectious agent. The progressive weakness that occurs some 30 to 40 years after recovery from polio should not be confused with PMA, as already indicated. Finally, we have had occasion to see patients who, many years after a severe electrical injury that passed through the region of the cervical cord, developed a progressive and severe amyotrophy of the arms; other such extraordinary cases are known but the concordance is considered coincidental by most authorities (see Chap. 42).


Neurology_Adams

Neurology_Adams. The effect of available treatment for any of the motor neuron diseases is modest. A small number of drugs, however, have been developed: riluzole, edaravone, and masitinib. Supportive measures, however, are exceedingly important. In initial office visits, it has been our practice to give the patient some idea of the seriousness of the condition; but in early discussions we avoid the devastating statement that ALS is invariably fatal. Typically, patients and family members will ask explicitly about these matters in subsequent visits; such data as are appropriate to the patient’s circumstances and character can be conveyed at that time, usually with the caveat that any individual may outlive the standard survival statistics.


Neurology_Adams

Neurology_Adams. The antiglutamate agent riluzole, when given orally, was shown by Bensimon and colleagues to slow the progression of ALS and improve survival in patients with disease of bulbar onset; it prolonged survival by 3 months. Antioxidants have slowed the clinical progress of ALS in limited and unconfirmed trials. Masitinib is a tyrosine kinase inhibitor that has been tried in a number of degenerative disorders and is under investigation in ALS. Some of these claims have been confirmed in several followup studies, although again, the benefit has been marginal. Several additional agents are reported to have been effective in genetic models of ALS. Among the long list of agents that have claimed, but ultimately failed, to help ALS are guanidine hydrochloride, injections of cobra venom, gangliosides, interferons, high-dose intravenous cyclophosphamide, and thyrotropin-releasing hormone.


Neurology_Adams

Neurology_Adams. With regard to symptomatic treatment, an attempt can be made to reduce spasticity with medications, such as baclofen or tizanidine, or by subarachnoid infusions of baclofen via an implanted lumbar pump. Initial intrathecal test doses are given to predict a response to the pump infusions of baclofen, but this test may fail; consequently, in severe cases it may be advisable to proceed with a constant infusion for several days. Some degree of improved comfort from a reduction in the extreme rigidity is usually the most that can be expected. Partial relief from spasticity may also be afforded by the use of benzodiazepines or sometimes dantrolene. These approaches are most suitable for cases of primary lateral sclerosis, which can be expected to progress slowly and for a long period. The pseudobulbar syndrome can be ameliorated with dextromethorphan-quinidine compounds.


Neurology_Adams

Neurology_Adams. At all stages of ALS, physical therapy is useful in maintaining mobility, but overwork of the muscles leading to fatigue and cramps should be avoided. Physical therapy is invaluable, for example, for avoiding contractures of the fingers and shoulders. Occupational therapy is likewise helpful, particularly assessments of the patient’s function in the home.


Neurology_Adams

Neurology_Adams. Important in the management of ALS is periodic monitoring of respiratory function. We have typically performed pulmonary function tests every few months after the first year or so of illness. Our experience has been that the vital capacity in cubic centimeters can be estimated by multiplying the highest number to which a patient can count with 1 deep breath by 100. Thus, the ability to count to 25 with a full effort in a single breath corresponds to a vital capacity of approximately 2.5 L. Significant practical advances have been made in the respiratory management of ALS. The introduction of bilevel positive airway pressure (BiPAP) has allowed patients to sleep better and reduce daytime somnolence. Many patients do not initially tolerate the device, usually because of maladjusted face masks or excessive applied airway pressures. Almost always, a seasoned pulmonary technologist can find solutions to these problems. It is appropriate to begin BiPAP at (or before) the earliest sign of


Neurology_Adams

Neurology_Adams. or excessive applied airway pressures. Almost always, a seasoned pulmonary technologist can find solutions to these problems. It is appropriate to begin BiPAP at (or before) the earliest sign of carbon dioxide retention, a state that is heralded by disruption of sleep, nightmares, early morning headaches, and daytime drowsiness. With noninvasive respiratory assistance, it may be possible to defer tracheostomy for months or years. Ultimately, as the diaphragm fails, BiPAP is needed not only at night but also during the day. As BiPAP use approaches 20 to 24 h per day, patients must usually address the difficult question of tracheostomy and mechanical ventilation. We broach this subject early enough in the course of the disease to allow ample time for discussion and reflection. In practice, most patients elect not to undergo tracheostomy and full ventilation.


Neurology_Adams

Neurology_Adams. Another important issue regards nutrition. As oropharyngeal palsy progresses, food should be cut into small pieces and dry foods, such as toast should be avoided; milk shakes and preparations of the same consistency are ideal at this stage. Speech therapists are capable of teaching patients methods to adapt to declining bulbar function and at the same time minimizing aspiration. Ultimately, in our experience, most ALS patients will need a feeding tube to maintain normal hydration and caloric intake. Although we adopt a neutral position in discussions with patients regarding mechanical ventilation, we tend to urge patients to undergo placement of a feeding tube at the appropriate time. This presumably increases survival and improves quality of life by preventing dehydration and recurrent aspiration. Laparoscopic and radiologic technologies for the placement of a gastrostomy tube render the procedure swift and nearly painless. Some patients have tubes inserted as outpatients and then


Neurology_Adams

Neurology_Adams. aspiration. Laparoscopic and radiologic technologies for the placement of a gastrostomy tube render the procedure swift and nearly painless. Some patients have tubes inserted as outpatients and then start gastric feeding within 1 or 2 days.


Neurology_Adams

Neurology_Adams. Other devices, often guided by the physical and occupational therapist, may be of great assistance to the patient and family as the disease progresses. These include a mechanized bed and structural accommodations in the home that facilitate entry of a wheelchair and the safe use of the bath or shower as well as thick-handled utensils. Ambulation aids, beginning with simple canes (first 1, then 2) followed by a walker (preferably with basket and seat) and then a wheelchair (manual or electric) are of value in maintaining a sense of independence and ensuring safety. The American Academy of Neurology has published guidelines for management that have been of aid to patients and physicians; they emphasize the complex and multidisciplinary needs of ALS patients (see Miller et al 2009a and 2009b). Genetic Forms of Progressive Muscular Atrophy


Neurology_Adams

Neurology_Adams. Genetic Forms of Progressive Muscular Atrophy These diverse diseases have a clear heredofamilial nature, usually monogenic, unlike ALS, in which there is an inherited factor in only some cases. They are mostly the concern of pediatric neurology but some have later onset and are mistaken for acquired neuromuscular disorders. Spinal Muscular Atrophy (Werdnig-Hoffman Disease, SMN Mutation) History The classic form of spinal muscular atrophy was described by Werdnig in 1891 and 1894, by Hoffmann in 1893 and, at about the same time, by Thomsen and Bruce. The cases described by these authors were all in infants. Further clinical analyses, however, indicated the inadequacy of this narrow grouping for the large number of spinal muscular atrophies. Brandt, in his study of 112


Neurology_Adams

Neurology_Adams. Danish patients, found that in about one-third the weakness was present at birth, and in 97 the onset was in the first year of life; in 9 patients, the disease was not recognized until after the first year of life. In 1956,


Neurology_Adams

Neurology_Adams. Walton, and later Wohlfart and colleagues and Kugelberg and Welander (see below), identified milder forms of spinal muscular atrophy in which the onset was between 2 and 17 years and walking was still possible in adult life. Byers and Banker, in a study of 52 patients, subdivided them into 3 groups on the basis of age of onset; in 1 group the disease was recognized at birth or in the first month or two of life; in a second, between 6 and 12 months; and in a third, after the first year. In their last group, it was not unusual for the patient to survive into adolescence and adult life. In a few of the late-onset types, signs of corticospinal tract involvement are conjoined, and Bonduelle has also included some patients with areflexia, pes cavus, Babinski signs, choreiform movements, and developmental delay in this group. More recently, the designations SMA I, II, and III have been introduced, based on the age of onset and genetic variant (see Table 38-7).


Neurology_Adams

Neurology_Adams. Genetic aspects of spinal muscular atrophies Familial spinal muscular atrophy that begins in infancy and childhood is inherited mainly as an autosomal recessive trait. All the SMA phenotypes in children have been mapped to mutations affecting the “survival of motor neuron” (SMN1) gene. The SMN protein participates in forming protein-RNA complexes (small nuclear ribonucleoproteins and RNA) that are essential for gene splicing. Within the SMN locus there are 2 alleles: SMN1, which generates a full-length, fully functional form of SMN, and SMN2, which makes a truncated, partially functional SMN. The latter can partially compensate for the loss of SMN1. Making matters more complex, individuals vary in the number copies of SMN2. As a result, disease due to loss of both copies of SMN1 causes very severe SMA in individuals who carry only one copy of SMN2, while those with multiple copies of SMN2 have milder disease. Thus, the amount of SMN2 protein determines the severity and time of onset


Neurology_Adams

Neurology_Adams. severe SMA in individuals who carry only one copy of SMN2, while those with multiple copies of SMN2 have milder disease. Thus, the amount of SMN2 protein determines the severity and time of onset of disease.


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Neurology_Adams. Although affected siblings demonstrate very similar clinical patterns of disease, the same mutation may give rise to very different phenotypes in different families, so that additional modifying posttranscriptional or nongenetic attributes must be playing a role. Less often, autosomal dominant and X-linked patterns of inheritance have been found, resulting from mutations in UBA1, usually in adults. A rare autosomal dominant adult form is the result of mutations in VABP and a form that affects only the legs is associated with mutations in DYNC1H1.


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Neurology_Adams. Clinical manifestations of Werdnig-Hoffmann disease (SMA 1) The most frequent form of these spinal muscular atrophies, the severe infantile type, is a common disease, occurring once in every 20,000 live births. After cystic fibrosis, it is also the most frequent cause of death from a recessively inherited disease. Characteristically the infant, usually born normally, is noted from birth to be unnaturally weak and limp (“floppy”). Some mothers report that fetal movement in utero had been less than expected or lacking altogether. In severe cases, arthrogryposis at the ankles and wrists or dislocation of the hips is noted at birth (arthrogryposis and its differential diagnosis is discussed in Chap. 45 in the section on the congenital neuromuscular disorders). The muscle weakness in these children is generalized from the beginning, and death comes early, usually within the first year. Other infants seem to develop normally for several months before the weakness becomes apparent. In these,


Neurology_Adams

Neurology_Adams. is generalized from the beginning, and death comes early, usually within the first year. Other infants seem to develop normally for several months before the weakness becomes apparent. In these, the trunk, pelvic, and shoulder-girdle muscles are at first disproportionately affected, while the fingers and hands, toes and feet, and cranial muscles retain mobility. Hypotonia accompanies the weakness, and because passive displacement of articulated parts in testing muscle tone is easier to judge than power of contraction at this early age, it may be singled out as the dominant clinical characteristic. As a rule, the tendon reflexes are unobtainable. Volume of muscle is diminished but is difficult to evaluate in the infant because of the coverings of adipose tissue. Fasciculations are seldom visible except sometimes in the tongue. Perception of tactile and painful stimuli is undiminished, and emotional and social development measures up to age.


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Neurology_Adams. As the months pass, the weakness and hypotonia progress gradually and spread to all the skeletal muscles except the ocular ones. Intercostal paralysis with a degree of collapse of the chest is the rule. Respiratory movements become paradoxical (abdominal protrusion with chest retraction). The cry becomes feeble, and sucking and swallowing are less efficient. Such infants are unable to sit unless propped, and they cannot hold up their heads without support and cannot roll over or support their weight when placed on their feet. Their posture is characteristic: arms abducted and flexed at the elbow, legs in the “frog position” with external rotation and abduction at hips and flexion at hips and knees. If the effects of gravity are removed, all muscles continue to contract; that is there is paresis, not paralysis. Until late in the illness, these children appear bright-eyed, alert, and responsive.


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Neurology_Adams. Infants in whom the disease becomes apparent only after several months of life have a less-rapid decline than those affected in utero or at birth. Some of the former become able to sit and creep and even to walk with support; those with later onset may survive for several years and even into adolescence or early adult life, as already mentioned. Laboratory data of confirmatory value are few. Muscle enzymes in the serum are usually normal or rarely elevated. The EMG, if performed at a late enough stage of development, displays fibrillations, proving the denervative basis of the weakness. Motor unit potentials are diminished in number and, in the more slowly evolving cases, some are larger than normal (giant or polyphasic potentials reflecting reinnervation). Motor nerve conduction velocities are normal or fall in the low-normal range (these are normally slower in infants than in adults). Electrophysiologic studies performed in the first few months of life may give ambiguous results.


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Neurology_Adams. Pathologic findings Muscle biopsy after 1 month of age reveals a typical picture of group atrophy; shortly after birth this change is difficult to discern. Aside from denervative atrophy, the essential abnormalities are in the anterior horn cells in the spinal cord and the motor nuclei in the lower brainstem. Nerve cells are greatly reduced in number, and many of the remaining ones are in varying stages of degeneration; a few are chromatolytic and contain cytoplasmic inclusions. It is not unusual to see figures of neuronophagia. There is replacement gliosis and secondary degeneration in roots and nerves. Other systems of neurons, including the corticospinal and corticobulbar systems, are entirely unaffected.


Neurology_Adams

Neurology_Adams. Differential diagnosis The major problem in diagnosis is to distinguish Werdnig-Hoffmann disease from an array of other diseases that cause hypotonia and delayed motor development in the neonate and infant. The list of disorders that imitates spinal muscular atrophy constitutes a large part of the differential diagnosis of the so-called floppy infant. The congenital myopathies (as described in Chap. 45), the glycogenoses, neonatal myasthenia gravis, Prader-Willi syndrome, and disorders of fatty acid metabolism frequently present in this way. The preservation of tendon reflexes and relative lack of progression of muscle weakness distinguish the latter disorders. Because of the gravity of the diagnosis, genetic testing or muscle biopsy should be performed if there is any suspicion of spinal muscular atrophy. If studied properly, the biopsy usually yields the correct diagnosis.


Neurology_Adams

Neurology_Adams. Clinical disorders more or less similar to the spinal muscular atrophies may be identified occasionally in certain hereditary metabolic diseases. For example, Johnson and coworkers have described a patient who began experiencing weakness of the legs, cramping, and fasciculations during adolescence in what proved to be a variant of hexosaminidase A (GM2) deficiency, and biopsy of rectal mucosa showed nerve cells with the typical membranous cytoplasmic bodies of Tay-Sachs disease. Others have reported similar cases. A progressive motor neuron or motor nerve disorder has also been observed in glycogen storage disease affecting anterior horn cells. Motor nerve fibers also suffer damage in metachromatic and globoid body leukoencephalopathies.


Neurology_Adams

Neurology_Adams. Certain forms of muscular dystrophy, notably myotonic dystrophy, which is about twice as frequent as Werdnig-Hoffmann disease, may become manifest in the neonatal period and interfere with sucking and motor development (see Chap. 45). As a rule, the weakness is not as severe or diffuse as that in Werdnig-Hoffmann disease. The mother, but not the child, may display myotonia, either elicitable clinically or, if more subtle, with EMG recording. Also, a number of polyneuropathies may cause a serious degree of weakness in early childhood. Unfortunately, in respect to the latter, adequate sensory testing is not possible because of the patient’s age, but the CSF protein is often elevated. Again, diagnosis is greatly facilitated by nerve-muscle biopsy and measurement of nerve conduction velocities. These velocities are reduced but must be interpreted with caution because of incomplete development of axons and of myelination in the first months of life. The needle EMG examination shows subtle


Neurology_Adams

Neurology_Adams. These velocities are reduced but must be interpreted with caution because of incomplete development of axons and of myelination in the first months of life. The needle EMG examination shows subtle signs of denervation that cannot be easily distinguished from the finding in the spinal muscular atrophies. Examination of parents and siblings may disclose a clinically inapparent neuropathy. Polymyositis of childhood may also simulate both muscular dystrophy and motor neuron disease. Finally, nemaline and central core myopathy can manifest in infancy and early childhood and cause a floppy child syndrome.


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Neurology_Adams. Developmental delay with a flaccid rather than spastic weakness of the limbs is another major category of disease that must be distinguished. These include Down syndrome, cretinism, Prader-Willi syndrome, and achondrodysplasia. It should be commented that very sick children with celiac disease, cystic fibrosis, and other chronic diseases may be hypotonic to the point of simulating neuromuscular disease. Usually speech is not delayed and tendon reflexes are preserved in these purely medical states, and strength returns as the medical problem is corrected. Also, certain of the polioencephalopathies and leukodystrophies may weaken muscles and abolish tendon reflexes, but usually there is evidence of cerebral involvement.


Neurology_Adams

Neurology_Adams. There remains, after the assiduous study of the “floppy infant,” a group of cases of hypotonia and motor underdevelopment that cannot be classified. The term amyotonia congenita (Oppenheim) was once applied to this entire group but is now obsolete. Walton proposed the term benign congenital hypotonia to designate patients who manifest limp and flabby limbs in infancy and a delay in sitting up and walking but who improve gradually, some completely and others incompletely. It is likely that among this group there are examples of congenital myopathy that await differentiation by application of modern histochemical, ultrastructural, and genetic techniques.


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Neurology_Adams. Treatment Two novel treatments have been remarkable developments in this otherwise dismal field. One, nusinersen, is an antisense oligonucleotide that modifies splicing of SMN2 to result in increased production of SMN protein in motor neurons and compensate for the mutated SMN1 (Finkel et al). It is delivered by repeated intrathecal injection. It was shown to be effective in later onset SMA (types 2 and 3) as noted below. The second, is gene therapy with an adeno-associated viral vector containing SMN1, delivered as a single intravenous injection (Mendell et al). This has induced SMN expression. Both of these have been tested in small numbers of patients and in some cases, against historical controls.


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Neurology_Adams. Chronic childhood and juvenile proximal spinal muscular atrophy (Kugelberg-Welander syndrome, SMA 3 and Dubowitz syndrome SMA 2) This is a somewhat different form of heredofamilial spinal muscular atrophy, which, as the name indicates, involves the proximal muscles of the limbs predominantly and is only slowly progressive. It was first separated from other forms of motor system disease and from muscular dystrophy by Wohlfart et al and by Kugelberg and Welander in the mid-1950s. In about one-third of the cases the onset is before 2 years of age, and in half, between 3 and 18 years. Males predominate, especially among patients with juvenile and adult onset. The usual form of transmission is by an autosomal recessive pattern; most cases result from mutations in the SMN gene; as mentioned, multiple copies of the SMN2 gene partly rescue the loss of SMN1 and lead to this milder form of disease. Families with dominant and sex-linked inheritance have also been described.


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Neurology_Adams. The disease begins insidiously, with weakness and atrophy of the pelvic girdle and proximal leg muscles, followed by involvement of the shoulder girdle and upper arm muscles. Unlike the sporadic form of spinal muscular atrophy, the Wohlfart-Kugelberg-Welander variety (also listed in other books and monographs as Kugelberg-Welander disease) is bilaterally symmetrical from the beginning, and fasciculations are observed in only half the cases. Ultimately, the distal limb muscles are involved and tendon reflexes are lost. Bulbar musculature and corticospinal tracts are spared, although Babinski signs and an associated ophthalmoplegia (presumably neural) have been reported in rare instances. The presence of fasciculations and the EMG and muscle biopsy findings—all of which show the characteristic abnormalities of neural atrophy—permit distinction from muscular dystrophy. Cases that have been examined postmortem have shown loss and degeneration of the anterior horn cells.


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Neurology_Adams. The disease progresses very slowly, and some patients survive to old age without serious disability. In general, the earlier the onset, the less favorable the prognosis; however, even the most severely affected patients retain the ability to walk for at least 10 years after the onset. Admittedly, it is difficult to make a sharp distinction between these cases of Wohlfart-Kugelberg-Welander disease and certain milder instances of Werdnig-Hoffmann disease with onset in late infancy and early childhood and prolonged survival (Byers and Banker). A form that is intermediate between the severe Werdnig-Hoffman type and the milder Wohlfart- Kugelberg-Welander is termed Dubowitz syndrome and designated SMA 2. It is in this disorder that the intrathecal administration of nusinersen, the antisense oligonucleotide referenced above, has been shown to be effective (Mercuri et al). Kennedy Disease (X-Linked Bulbospinal Muscular Atrophy, AR Mutation)


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Neurology_Adams. An unusual pattern of distal muscular atrophy with prominent bulbar signs and, less often, ocular palsies was described by Kennedy and coworkers. The onset has varied from childhood to adult age, but symptoms typically begin in the third decade. The condition has an X-linked pattern of inheritance; female carriers may occasionally be mildly symptomatic. The proximal shoulder and hip musculature are involved first by weakness and atrophy, followed in about half of patients by dysarthria and dysphagia. Muscle cramps or twitching often precedes weakness. Facial fasciculations and mild weakness are characteristic and may be striking. The tendon reflexes become depressed and may be absent; a mild sensory neuropathy is almost universal. In the family described by Kaeser, which is representative of the disease as described by others, 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, that is scapuloperoneal; it may therefore be mistaken for muscular


Neurology_Adams

Neurology_Adams. of the disease as described by others, 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, that is scapuloperoneal; it may therefore be mistaken for muscular dystrophy. Two-thirds of patients have gynecomastia, a feature that may first identify affected men in a kindred; oligospermia and diabetes are additional associations; therefore, the presence of genuine progeny virtually excludes the disease in a male. The CK level is elevated, sometimes tenfold, and physiologic studies reveal denervation and reinnervation as well as indications of a mild sensory neuropathy.


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Neurology_Adams. As in Huntington disease and certain of the spinocerebellar atrophies, the genetic defect is a CAG expansion, in this case in the gene (AR) that codes for the androgen receptor on the short arm of the X-chromosome (La Spada et al; see Table 38-7). Indeed, the first reported polyglutamine disease was Kennedy syndrome. Lengthened sequences correlate with an earlier age of onset (anticipation, as in Huntington disease) but have no relation to the severity of disease. Androgen receptors have been found on motor neurons of the spinal cord; the subpopulation of motor neurons that is susceptible to both Kennedy syndrome and ALS express abundant surface androgen receptors, but it is not clear whether this finding has direct pathogenic significance. Neuronal inclusions have been described, composed of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide


Neurology_Adams

Neurology_Adams. of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide sequence. Prenatal diagnosis and identification of female carriers are also possible by this method.


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Neurology_Adams. Progressive Bulbar Palsy of Childhood (Fazio-Londe Disease)


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Neurology_Adams. Fazio in 1892, and Londe in 1893, described the development of a progressive bulbar palsy in children, adolescents, and young adults. There is progressive paralysis of the facial, lingual, pharyngeal, laryngeal, and sometimes ocular muscles. The illness usually presents with stridor and respiratory symptoms, followed by facial diplegia, dysarthria, dysphagia, and dysphonia. These features become increasingly pronounced until the time of death some years later. In a few patients there is a late development of corticospinal signs and sometimes ocular palsies. Occasionally, jaw and oculomotor paresis appears, and in one case, there was progressive deafness. The disease is rare, only several dozen well-described examples had been recorded in the medical literature by 1992 (McShane et al). Inheritance may be autosomal dominant, as in Fazio’s original case, and rarely X-linked, but it is more likely to be autosomal recessive. Pathologic examination has shown a loss of motor neurons in the


Neurology_Adams

Neurology_Adams. may be autosomal dominant, as in Fazio’s original case, and rarely X-linked, but it is more likely to be autosomal recessive. Pathologic examination has shown a loss of motor neurons in the hypoglossal, ambiguus, facial, and trigeminal motor nuclei. In a few cases, the nerve cells in the ocular motor nuclei also were diminished. This disease, the 2 times we have encountered it, had to be differentiated from myasthenia gravis, a pontomedullary glioma, and brainstem multiple sclerosis.


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Neurology_Adams. The cause of the disease is interesting in that it results from mutations in SLC52A3, a riboflavin transporter, and some beneficial effect is derived from the administration of riboflavin (vitamin B2). The disease is allelic with Brown-Vialetto-Van Laere syndrome, another motor neuron degeneration, which includes deafness. Hereditary Forms of Spastic Paraplegia This disease was described by Seeligmuller in 1874 and later by Strümpell in Germany and Lorrain in France; it has now been identified in nearly every part of the world. The pattern of inheritance is usually autosomal dominant, less often recessive (one family has shown X-linked inheritance), and the onset may be at any age from childhood to the senium. Harding (1993) divided the disease into 2 groups, the more common one beginning before age 35 with a very protracted course and the other with a late onset (40 to 60 years). The latter type often shows sensory loss, urinary symptoms, and action tremor.


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Neurology_Adams. The clinical picture is that of a gradual development of spastic weakness of the legs with increasing difficulty in walking. The tendon reflexes are hyperactive and the plantar reflexes extensor. In the pure form of the disease, sensory and other nervous functions are entirely intact. If the onset is in childhood, as many cases are, the foot arches become exaggerated, the feet are shortened, and there is a tightening (pseudocontracture) of calf muscles, forcing the child or adolescent to “toe-walk.” This is a common orthopedic problem and may require surgical correction. In children, the legs appear to be underdeveloped, and in both children and adults they may become quite thin. Sometimes the knees are slightly flexed; at other times the legs are fully extended or hyperextended (genu recurvatum) and adducted. Weakness is variable and difficult to estimate. Sphincteric function is usually retained. Subtle sensory loss in the feet has been reported. The arms are variably involved. In


Neurology_Adams

Neurology_Adams. and adducted. Weakness is variable and difficult to estimate. Sphincteric function is usually retained. Subtle sensory loss in the feet has been reported. The arms are variably involved. In some patients, the arms appear to be spared even though the tendon reflexes are lively. In others, the hands are stiff, movements are clumsy, and speech is mildly dysarthric. Conjoined findings such as nystagmus, ocular palsies, optic atrophy, pigmentary macular degeneration, ataxia (both cerebellar and sensory), sensorimotor polyneuropathy, ichthyosis, patchy skin pigmentation, epilepsy, and dementia have all been described in isolated families (see further on).


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Neurology_Adams. The few available pathologic studies have shown that, in addition to degeneration of the corticospinal tracts throughout the spinal cord, there is thinning of the columns of Goll, mainly in the lumbosacral regions, and of the spinocerebellar tracts, even when no sensory abnormalities had been detected during life. These were the pathologic findings described by Strümpell in his original (1880) report of 2 brothers with spastic paraplegia; one of them, in addition, had a cerebellar syndrome, but again, there were no sensory abnormalities. A reduction in the number of Betz and anterior horn cells has also been reported. Genetic aspects of hereditary spastic paraplegia


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Neurology_Adams. Numerous genetic mutations have given rise to this disease. As of this writing, there were at least 52 hereditary spastic paraplegia (HSP) loci some of which are shown in Table 38-8. The disease types have been renamed under the designation “SPG” (for spastic paraplegia) and numbered in order of discovery of the associated gene. The common uncomplicated autosomal dominant form of disease has been linked to mutations in many proteins, the most common being (proteins in parentheses) SPAST (spastin) and ALT1 (atlastin); and the common recessive varieties, are in SPG7 (paraplegin); and X-linked in L1CAM and PLP1 (proteolipid protein). The common spastin variety, associated with a mutation on chromosome 2p, results in great variability of clinical presentation within and among families (see Nielsen et al). A high frequency of partial deletions of the SPAST gene has been found. The possible subcellular mechanisms by which these mutations cause degeneration of the corticospinal tracts have


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Neurology_Adams. et al). A high frequency of partial deletions of the SPAST gene has been found. The possible subcellular mechanisms by which these mutations cause degeneration of the corticospinal tracts have been reviewed by Blackstone.


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Neurology_Adams. Differential diagnosis In the diagnosis of this disorder, one should consider an indolent spinal cord or foramen magnum tumor, cervical spondylosis, a spinal from of multiple sclerosis (this was the clinical diagnosis in Strümpell’s original cases), Chiari malformation, compression of the cord by a variety of congenital bony malformations at the craniocervical junction, and a number of chronic myelitides, among them, lupus erythematosus, sarcoidosis, HIV myelopathy, adrenomyeloneuropathy, primary lateral sclerosis (described earlier in this chapter), hypocupric myelopathy, spinal arteriovenous dural fistula, and especially, tropical spastic paraparesis (caused by the HTLV-1 virus as discussed in Chap. 32). Variants of Familial Spastic Paraplegia


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Neurology_Adams. The literature contains a large number of descriptions of familial spastic paraplegia combined with other neurologic abnormalities. Some of the syndromes had developed early in life in conjunction with moderate degrees of developmental delay. In these, the rest of the neurologic picture appeared many years after birth and was progressive. Some idea of the number of these “hereditary paraplegia-plus” syndromes and the diverse combinations in which they may be present is conveyed in the review by Gout and colleagues. Again, it is hardly possible to describe each of these symptoms in any degree of detail. The list below includes the best-known entities but all are rare. But if the term hereditary spastic paraplegia is to have any neurologic significance, it should be applied only to the pure form of the progressive syndrome. The more common “atypical” or “syndromic” cases—with amyotrophy, cerebellar ataxia, tremors, dystonia, athetosis, optic atrophy, retinal degeneration, amentia, and


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Neurology_Adams. form of the progressive syndrome. The more common “atypical” or “syndromic” cases—with amyotrophy, cerebellar ataxia, tremors, dystonia, athetosis, optic atrophy, retinal degeneration, amentia, and dementia—should be put in separate categories and their identity retained for nosologic purposes until such time as additional biochemical and genetic data related to pathogenesis are forthcoming. The gene mutations found in some of the variant types were summarized by Fink, but—as with all types of uncomplicated and complicated hereditary spastic paraplegia—the mechanisms of neuronal loss are not known. To be separated from these cases are all the congenital nonprogressive types of spastic diplegia and athetosis. The following list includes the best-known entities: 1. Hereditary spastic paraplegia with ataxia (Ferguson-Critchley syndrome, SAX1 mutation) This syndrome is one of a collection of leg spasticity and generalized ataxia syndrome that may also be characterized by a disorder of


Neurology_Adams

Neurology_Adams. with ataxia (Ferguson-Critchley syndrome, SAX1 mutation) This syndrome is one of a collection of leg spasticity and generalized ataxia syndrome that may also be characterized by a disorder of gaze, or optic atrophy. Most impressive are the manifestations of spinocerebellar ataxia beginning during the fourth and fifth decades of life, accompanied by weakness of the legs, alterations of mood, pathologic crying and laughing, dysarthria and diplopia, dysesthesias of limbs, and poor bladder control. The tendon reflexes are lively, with bilateral Babinski signs. Sensation is diminished distally in the limbs. The whole picture resembles a chronic progressive form of multiple sclerosis. In other cases, running through several generations of a family, the extrapyramidal features were more striking; such cases overlap with the following syndromes. A dominant form of the disease is due to a mutation in SAX1.


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Neurology_Adams. 2. Hereditary spastic paraplegia with extrapyramidal features Action and static tremors, parkinsonian rigidity, dystonic tongue movement, and athetosis of the limbs have all been conjoined with spastic paraplegia. Gilman and Romanul have reviewed the literature on this subject. In the authors’ experience, the picture of parkinsonism with spastic weakness and other corticospinal signs has been the most frequent combination. 3. Hereditary spastic paraplegia with optic atrophy (OPA3 mutation) This is known as Behr syndrome or optic atrophy-ataxia syndrome, since cerebellar signs are usually conjoined. Some patients also have athetosis. The syndrome is transmitted as an autosomal recessive trait, with onset in infancy and slow progression. The mutation is in OPA3. There may be a relationship to decreased excretion of 3-methylglutaconic aciduria of an optic atrophy and cataract syndrome (Costeff syndrome).


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Neurology_Adams. 4. Hereditary spastic paraplegia with macular degeneration (Kjellin syndrome, SPG11 and SPG15 mutations) Spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration constitutes the syndrome described in 1959 by Kjellin. Although the developmental delay is stationary, the spastic weakness and retinal changes are of late onset and progressive. Mutations have been found in SPG11 and SPG15. 5. Hereditary spastic paraplegia with developmental delay or dementia Many of the children with progressive spastic paraplegia either have been developmentally delayed since early life or have appeared to regress mentally as other neurologic symptoms developed. Examples of this syndrome and its variants are too numerous to be considered here but are contained in the review by


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Neurology_Adams. Gilman and Romanul. The autosomal recessive syndrome of Sjögren-Larsson, with the onset in infancy of spastic weakness of the legs in association with developmental delay, stands somewhat apart from the others in this large group because of the associated ichthyosis. The mutation for the latter is in ALDH3A2 that codes for fatty aldehyde dehydrogenase. This relates to both dry skin, itchy and discolored skin, and the myelinopathy that characterize Sjögren-Larsson syndrome.


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Neurology_Adams. 6. Hereditary spastic paraplegia with polyneuropathy Our colleagues had observed several patients in whom a sensorimotor polyneuropathy was combined with unmistakable signs of corticospinal disease. The age of onset was in childhood or adolescence, and the disability progressed to the point where the patient was chairbound by early adult life. In 2 of the cases, a sural nerve biopsy revealed a typical hypertrophic polyneuropathy; in a third case there was only a depletion of large myelinated fibers. The syndrome resembles the myeloneuropathy of adrenoleukodystrophy. 7. Spastic paraparesis with distal muscle wasting (Troyer syndrome, SPG20 mutation) This disorder is transmitted as an autosomal recessive trait in the Amish population. Onset is in childhood with amyotrophy of the hands, followed by spasticity and contractures of the lower limbs. Cerebellar signs (mild), athetosis, and deafness may be added. The mutation is in SPG20.


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Neurology_Adams. SYNDROME OF BLINDNESS DUE TO DEGENERATIVE DISORDERS (SEE CHAP. 12) There are 2 main classes of progressive blindness in children, adolescents, and adults: progressive optic neuropathy and retinal degenerations (retinitis pigmentosa and tapetoretinal macular degeneration). Of course, there are many congenital anomalies and retinal diseases beginning in infancy that result in blindness and microphthalmia. Some of those of neurologic interest were described briefly in connection with the hereditary spastic paraplegias and in Chap. 12.


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Neurology_Adams. History Although familial amaurosis was known in the early 18th century, it was Leber, in 1871, who gave the definitive description of this disease and traced it through many genealogies. The family studies of Nikoskelainen and coworkers indicate that all daughters of carrier mothers become carriers themselves, a type of transmission that is determined by inheritance of defective mitochondrial DNA from the mother (Wallace et al). Common to all cases is the presence of a pathogenic mitochondrial DNA abnormality (Riordan-Eva et al), but the defect may occur at one of several sites as discussed in Chap. 36. Thus, Leber optic atrophy has been added to the growing list of mitochondrial diseases. Variants in approximately 20 genes have been detected, together accounting for about half of cases.


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Neurology_Adams. This mitochondrial disease should not be mistaken for Leber’s congenital amaurosis, a retinal degeneration with a mutation in RPE65 that affects photoreceptors and causes infantile blindness. The latter disease assumes importance in part because it has an established gene therapy with some efficacy.


Neurology_Adams

Neurology_Adams. Clinical features In most patients, the visual loss begins between 18 and 25 years of age, but the range of age of onset is much broader. Usually the visual loss has a fairly rapid onset and a subacute evolution suggesting a retrobulbar neuritis; moreover, in these instances, aching in the eye or brow may accompany the visual loss, just as it does in the demyelinative variety. Subjective visual phenomena are reported by some. Usually both eyes are affected simultaneously, although in many, one eye is affected first, followed by the other after an interval of several weeks or months. In practically all cases, the second eye is affected within a year of the first. In the unimpaired eye, abnormalities of visual evoked potentials may antedate impairment of visual acuity (Carroll and Mastaglia).


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Neurology_Adams. Once started, the visual loss progresses over a period of weeks to months. Characteristically, central vision is lost before peripheral, and there is a stage at which bilateral central scotomata are readily demonstrated. Early on, perception of blue-yellow is deficient, while that of red and green is relatively preserved. In the more advanced stages, however, the patients are totally color-blind. Constriction of the fields may be added later. At first there may be swelling and hyperemia of the discs, but soon they become atrophic. Peripapillary vasculopathy, consisting of tortuosity and arteriovenous shunting, is the primary structural change; this has been present also in asymptomatic offspring of carrier females.


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Neurology_Adams. As visual symptoms develop, fluorescein angiography shows shunting in the abnormal vascular bed, with reduced filling of the capillaries of the papillomacular bundle. Although patients are left with dense central scotomata, it is of some importance that the visual impairment is seldom complete; in some patients, relative stabilization of visual function occurs. In a few, there may be a surprising improvement. Examination of the optic nerve lesion shows the central parts of the nerves to be degenerated from papillae to the lateral geniculate bodies, that is, the papillomacular bundles are particularly affected. Presumably axis cylinders and myelin degenerate together, as would be expected from the loss of nerve cells in the superficial layer of the retina. Both astrocytic glial and endoneurial fibroblastic connective tissue are increased. Tests for the 3 main mitochondrial mutations that give rise to the disorder are available.


Neurology_Adams

Neurology_Adams. Congenital optic atrophy (of which recessive and dominant forms are known), retrobulbar neuritis, and nutritional optic neuropathy are the main considerations in differential diagnosis. Retinitis Pigmentosa (See Also Chap. 12)


Neurology_Adams

Neurology_Adams. Retinitis Pigmentosa (See Also Chap. 12) This remarkable retinal abiotrophy, known to Helmholtz in 1851, soon after he invented the ophthalmoscope, usually begins in childhood and adolescence. Unlike the optic atrophy of Leber, which affects only the third neuron of the visual neuronal chain, retinitis pigmentosa affects all the retinal layers, both the neuroepithelium and pigment epithelium (see Fig. 12-2). The incidence of this disorder is 2 or 3 times greater in males than in females. Inheritance is more often autosomal recessive than dominant; in the former, consanguinity plays an important part, increasing the likelihood of the disease by approximately 20 times. Sex-linked types are also known. It is estimated that 100,000 Americans are afflicted with this disease. Mutations in approximately 60 genes have been associated with the disorder but the most commonly affected in autosomal dominant cases is RHO; in recessive cases, USH2A, and in X-linked cases, RPGR and RP2.


Neurology_Adams

Neurology_Adams. The first symptom is usually an impairment of twilight vision (nyctalopia). Under dim light, the visual fields tend to constrict; but slowly, as the disease progresses, there is permanent visual impairment in all degrees of illumination. The perimacular zones tend to be the first and most severely involved, giving rise to partial or complete ring scotomata. Peripheral loss sets in later. Usually both eyes are affected simultaneously, but cases are on record where 1 eye was affected first and more severely. Ophthalmoscopic examination shows the characteristic triad of pigmentary deposits that assume the configuration of bone corpuscles, attenuated vessels, and pallor of the optic discs. The pigment is caused by clumping of epithelial cells that migrate from the pigment layer to the superficial parts of the retina as the rod cells degenerate. The pigmentary change spares only the fovea, so that eventually the world is perceived by the patient as though he were looking through narrow


Neurology_Adams

Neurology_Adams. parts of the retina as the rod cells degenerate. The pigmentary change spares only the fovea, so that eventually the world is perceived by the patient as though he were looking through narrow tubes.


Neurology_Adams

Neurology_Adams. The many and diverse syndromes to which retinitis pigmentosa may be linked include oligophrenia, obesity, syndactyly, and hypogonadism (Bardet-Biedl syndrome); hypogenitalism, obesity, and mental deficiency (Laurence-Moon syndrome); Friedreich and other types of spinocerebellar and cerebellar ataxia; spastic paraplegia and quadriplegia with Laurence-Moon syndrome; neurogenic amyotrophy, myopia, and color-blindness; polyneuropathy and deafness (Refsum disease); deaf mutism; Cockayne syndrome and Bassen-Kornzweig disease; and several mitochondrial diseases, particularly progressive external ophthalmoplegia and Kearns-Sayre syndromes.


Neurology_Adams

Neurology_Adams. This is a bilaterally symmetrical, slowly progressive macular degeneration, differentiated from retinitis pigmentosa by Stargardt in 1909. In essence, it is a hereditary (usually autosomal recessive) tapetoretinal degeneration or dystrophy (the latter term being preferred by Waardenburg), with onset between 6 and 20 years of age, rarely later, and leading to a loss of central vision. The macular region becomes gray or yellow-brown with pigmentary spots, and the visual fields show central scotomata. Later the periphery of the retina may become dystrophic. The lesion is well visualized by fluorescein angiography, which discloses a virtually pathognomonic “dark choroid” pattern. Activity in the electroretinogram is diminished or abolished. Both recessively inherited Stargardt disease and the closely related cone-rod dystrophy have been linked to mutations of ABCA4 or ELOVL4 the former codes for a transporter protein (termed ABCR) of the photoreceptor.


Neurology_Adams

Neurology_Adams. This disease, with its selective loss of cone function, is in a sense the inverse of retinitis pigmentosa. According to Cohan and associates, it may be associated with epilepsy, Refsum syndrome, Kearns-Sayre syndrome, Bassen- Kornzweig syndrome, or Sjögren-Larsson syndrome, or with spinocerebellar and other forms of cerebellar degeneration and familial paraplegia. SYNDROME OF CONGENITAL OR PROGRESSIVE DEAFNESS (SEE CHAP. 14)


Neurology_Adams

Neurology_Adams. SYNDROME OF CONGENITAL OR PROGRESSIVE DEAFNESS (SEE CHAP. 14) There is an impressive group of hereditary, progressive cochleovestibular atrophies that are linked to degenerations of the nervous system. These were the subject of an authoritative review by Konigsmark and are summarized below. His clinical classification has been eclipsed by genetic findings but still serves as a useful guide. Such neurotologic syndromes must be set alongside a group of 5 diseases that affect the auditory and vestibular nerves exclusively: dominant progressive nerve deafness; dominant low-frequency hearing loss; dominant midfrequency hearing loss; sex-linked, early-onset neural deafness; and hereditary episodic vertigo and hearing loss. The last of these is of special interest to neurologists because both balance and hearing are affected.


Neurology_Adams

Neurology_Adams. It should be pointed out that in 70 percent of cases of hereditary deafness, there are no other somatic or neurologic abnormalities. To date, at least 3 separate autosomal mutations have been identified that are associated with a pure “nonsyndromic” type of hereditary deafness, the most common of which is in the connexin gene, as discussed in Chap. 14. A number of mitochondrial disorders have been associated with deafness alone as well as with a number of the better-characterized mitochondrial syndromes (see Chap. 34). The age of onset of hearing loss in the pure forms has been variable, extending well into adulthood.


Neurology_Adams

Neurology_Adams. Konigsmark has separated this overall category into 3 subgroups: patients with typical retinitis pigmentosa, those with Leber optic atrophy, and those with other retinal changes. With respect to retinitis pigmentosa, 4 syndromes are recognized in which retinitis pigmentosa appears in combination: with congenital hearing loss (Usher syndrome); with polyneuropathy (Refsum syndrome); with hypogonadism and obesity (Alstrom syndrome); and with dwarfism, mental retardation, premature senility, and photosensitive dermatitis (Cockayne syndrome).


Neurology_Adams

Neurology_Adams. Hereditary hearing loss with optic atrophy forms the core of 4 special syndromes: dominant optic atrophy, ataxia, muscle wasting, and progressive hearing loss (Sylvester disease); recessive optic atrophy, polyneuropathy, and neural hearing loss (Rosenberg-Chutorian syndrome); optic atrophy, hearing loss, and juvenile diabetes mellitus (Tunbridge-Paley syndrome); and opticocochleodentate degeneration with optic atrophy, hearing loss, quadriparesis, and developmental delay (Nyssenvan Bogaert syndrome).


Neurology_Adams

Neurology_Adams. Hearing loss has also been observed with other retinal changes, 2 of which are Norrie disease, with retinal malformation, hearing loss, and mental retardation (oculoacousticocerebral degeneration), and Small disease, with recessive hearing loss, mental retardation, narrowing of retinal vessels, and muscle atrophy. In the former, the infant is born blind, with a white vascularized retinal mass behind a clear lens; later the lens and cornea become opaque. The eyes are small, and the iris is atrophied. In the latter, the optic fundi shows tortuosity of vessels, telangiectases, and retinal detachment. The nature of the progressive generalized muscular weakness has not been ascertained. Susac syndrome should be considered in the broad differential diagnosis of this group of disorders. This is a microvasculopathy that causes characteristic changes in the white matter of the cerebral hemispheres, retinal vasculopathy, and progressive deafness as discussed in


Neurology_Adams

Neurology_Adams. Chap. 34. The later onset and progressive nature of deafness in this and several other syndromes are distinguished from forms of congenital deafness that are typical of the group discussed below. Hereditary Hearing Loss With Diseases of the Nervous System (See Table 14-1)


Neurology_Adams

Neurology_Adams. Hereditary Hearing Loss With Diseases of the Nervous System (See Table 14-1) There are numerous conditions, mostly of childhood and including developmental abnormalities, in which congenital deafness accompanies disease of the peripheral or central nervous system. Those associated with mitochondrial encephalopathies have already been mentioned. The other main types with autosomal inheritance include the following: 1. Hereditary hearing loss with epilepsy The seizure disorder is mainly one of myoclonus. In one dominantly inherited form, photomyoclonus is associated with mental deterioration, hearing loss, and nephropathy (Hermann disease). In May-White disease, also inherited as an autosomal dominant trait, myoclonus and ataxia accompany hearing loss. Congenital deafness and mild chronic epilepsy of recessive type have also been observed (Latham-Monro disease).


Neurology_Adams

Neurology_Adams. 2. Hereditary hearing loss and ataxia Here Konigsmark was able to delineate 5 syndromes, the first 2 of which show a dominant pattern of heredity, the last 3 a recessive pattern: piebaldism, ataxia, and neural hearing loss (Telfer-Sugar-Jaeger syndrome); hearing loss, hyperuricemia, and ataxia (Rosenberg-Bergstrom syndrome); ataxia and progressive hearing loss (Lichtenstein-Knorr syndrome); ataxia, hypogonadism, mental deficiency, and hearing loss (Richards-Rundle syndrome); ataxia, mental retardation, hearing loss, and pigmentary changes in the skin (Jeune-Tommasi syndrome).


Neurology_Adams

Neurology_Adams. 3. Hereditary hearing loss and other neurologic syndromes These include dominantly inherited sensory radicular neuropathy (Denny-Brown); progressive polyneuropathy, kyphoscoliosis, skin atrophy, eye defects (myopia, cataracts, atypical retinitis pigmentosa), bone cysts, and osteoporosis (Flynn-Aird syndrome); chronic polyneuropathy and nephritis (Lemieux-Neemeh syndrome); congenital pain asymbolia and auditory imperception (Osuntokun syndrome); and bulbopontine paralysis (facial weakness, dysarthria, dysphagia, and atrophy of the tongue with fasciculations) with progressive neural hearing loss. The onset of the last syndrome occurs at 10 to 35 years of age; the pattern of inheritance is autosomal recessive. The disease progresses to death. It resembles the progressive hereditary bulbar paralysis of Fazio-Londe except for the progressive deafness and loss of vestibular responses. Regrettably, in most of these syndromes, there are no data regarding labyrinthine function.


Neurology_Adams

Neurology_Adams. The details of these many syndromes are contained in Konigsmark’s review, of course, in the era before the genetic underpinnings of these diseases were accessible. The main syndromes are listed in Table 14-1 and are summarized above so as to increase awareness of the large number of hereditary-degenerative neurologic diseases for which the clue is provided by the detection of impaired hearing and labyrinthine functions. Abele M, Bûrk K, Schöls L, et al: The aetiology of sporadic adult-onset ataxia. Brain 125:961, 2002. AD 2000 Collaborative Group: Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): Randomised double-blind trial. Lancet 363:2105, 2004. Adams RD, van Bogaert L, van der Eecken H: Striato-nigral degeneration. J Neuropathol Exp Neurol 23:584, 1964. Adler CH, Beach TG, Hentz JG, et al: Low clinical diagnostic accuracy of early vs advanced Parkinson disease. Neurology 83:406, 2014.


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Neurology_Adams. Adler CH, Beach TG, Hentz JG, et al: Low clinical diagnostic accuracy of early vs advanced Parkinson disease. Neurology 83:406, 2014. Albert MS, Butters N, Brandt J: Patterns of remote memory in amnesic and demented patients. Arch Neurol 38:495, 1981. Allen N, Knopp W: Hereditary parkinsonism-dystonia with sustained control by l-dopa and anticholinergic medication. In: Eldridge R, Fahn S (eds): Advances in Neurology. Vol 14: Dystonia. New York, Raven Press, 1976, pp 201–215. Alzheimer A: Uber eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiatr 64:146, 1907. Alzheimer A: Uber eigenartige Krankheitsfalle des spateren Alters. Z Gesamte Neurol Psychiatr 4:356, 1911. Anderson JM, Hubbard BM: Definition of Alzheimer disease. Lancet 1:408, 1985. Andrew J, Fowler CJ, Harrison MJ: Stereotaxic thalamotomy in 55 cases of dystonia. Brain 106:981, 1983.


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Neurology_Adams. Anderson JM, Hubbard BM: Definition of Alzheimer disease. Lancet 1:408, 1985. Andrew J, Fowler CJ, Harrison MJ: Stereotaxic thalamotomy in 55 cases of dystonia. Brain 106:981, 1983. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT: Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631, 1992. Bannister R, Oppenheimer DR: Degenerative diseases of the nervous system associated with autonomic failure. Brain 95:457, 1972. Barbeau A: L-Dopa therapy in Parkinson’s disease. Canad Med Assoc J 101:59, 1969. Bateman RJ, Xiong C, Benzinger TLS, et al: Clinical and biomarker changes in dominantly inherited Alzheimer disease. N Engl J Med 367:367, 2012. Bates G: Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 361:1642, 2003. Beal MF, Richardson EP Jr: Primary lateral sclerosis: A case report. Arch Neurol 38:630, 1981.


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Neurology_Adams. Bates G: Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 361:1642, 2003. Beal MF, Richardson EP Jr: Primary lateral sclerosis: A case report. Arch Neurol 38:630, 1981. Behr C: Die komplizierte, hereditar-familiare Optikusatrophie des Kindesalters: Ein bisher nicht beschriebener Symptomkomplex. Klin Monatsbl Augenheilkd 47(Pt 2):138, 1909. Bejjani B, Damier P, Arnulf I, et al: Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 340:1476, 1999. Bensimon G, Lacomblez L, Meininger V: A controlled trial of riluzole in amyotrophic lateral sclerosis: ALS/Riluzole Study Group. N Engl J Med 330:585, 1994. Berg D, Postuma RB, Bloem B, et al: Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord 29:454, 2014. Bharucha NE, Bharucha EP, Bhabha SR: Machado-Joseph-Azorean disease in India. Arch Neurol 43:142, 1986.


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Neurology_Adams. Brice A: Genetics of Parkinson’s disease: LRRK2 on the rise. Brain 128:2760, 2005. Britton JW, Uitti RJ, Ahlskog JE, et al: Hereditary late-onset chorea without significant dementia. Neurology 45:443, 1995. Brown R, Al-Chalabi A: Amyotrophic lateral sclerosis. N Engl J Med 377, 162, 2017. Brown J, Lantos P, Stratton M, et al: Familial progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 56:473, 1993. Brun A, Passant U: Frontal lobe degeneration of non-Alzheimer type: Structural characteristics, diagnostic criteria, and relation to frontotemporal dementia. Acta Neurol Scand 168:28, 1996. Brzustowicz LM, Lehner T, Castilla LH, et al: Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 344:540, 1990. Burke RE, Dauer WT, Vonsattel JP. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485, 2008.


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Neurology_Adams. Dunlap CB: Pathologic changes in Huntington’s chorea, with special reference to corpus striatum. Arch Neurol Psychiatry 18:867, 1927. Egan MF, Kost H, Tariot PN, et al: Randomized trial of Verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 378:1691, 2018. Elias WJ, Huss D, Tiffini Voss NCS, et al: A pilot trial of focused ultrasound for essential tremor. N Engl J Med 369:640, 2013. Farmer TW, Wingfield MS, Lynch SA, et al: Ataxia, chorea, seizures, and dementia. Arch Neurol 46:774, 1989. Farrer LA, Conneally M: Predictability of phenotype in Huntington’s disease. Arch Neurol 44:109, 1987. Feany MD, Dickson DW: Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol 146:1388, 1995. Fearnley JM, Revesz T, Brooks DJ, et al: Diffuse Lewy body disease presenting with a supranuclear gaze palsy. J Neurol Neurosurg Psychiatry 54:159, 1991. Ferrer I, Santpere G, van Leeuwen FW: Argyrophilic grain disease. Brain 131, 1416, 2008.