Neurology_Adams

Neurology_Adams. these eye signs for a year or more after the onset of the illness. We have also followed several patients who had no disorder of eye movement during life but in whom the typical pathologic changes of PSP were found at autopsy. In one such patient, there was a subcortical type of dementia; in another, focal limb dystonia and parkinsonism. Furthermore, other degenerative conditions can manifest a supranuclear vertical gaze disorder, although never to the extent seen in PSP; these include corticobasal-ganglionic degeneration, Lewy body disease, Parkinson disease, and Whipple disease.


Neurology_Adams

Neurology_Adams. The gait disturbance and repeated falling have proved difficult to analyze, as discussed in Chap. 6. Walking becomes increasingly awkward and tentative; the patient has a tendency to totter and fall repeatedly, but has no ataxia of gait or of the limbs and does not manifest a


Neurology_Adams

Neurology_Adams. Romberg sign or orthostatic tremor. Some patients tend to lean and fall backward (retropulsion). One of our patients, a large man, fell repeatedly, wrecking household furniture as he went down, yet careful examination provided no clue as to the basic defect in this “toppling” phenomenon. Along with the oculomotor and balance disorders, there is a gradual stiffening and extension of the neck (in one of our patients it was sharply flexed in a manner consistent with camptocormia) but this is not an invariable finding. The face acquires a staring, “worried” expression with a furrowed brow (a result of the tonic contraction of the procerus muscle), made more striking by the paucity of eye movements. A number of our patients have displayed mild dystonic postures of a hand or foot, especially as the illness advanced but occasionally early on. The limbs may be slightly stiff and there are Babinski signs in a few cases.


Neurology_Adams

Neurology_Adams. The stiffness, slowness of movement, difficulty in turning and sitting down, and hypomimia may suggest a diagnosis of Parkinson disease. However, the facial expression of the PSP patient is more a matter of tonic grimace than of lack of movement, and the lack of tremor, the erect rather than stooped posture, and prominence of oculomotor abnormalities serve to distinguish the two disorders. The signs of pseudobulbar palsy are eventually prominent, and this feature, along with the eye movements, distinguishes the process most conspicuously from other degenerative conditions. The face becomes less expressive (“masked”), speech is slurred in a slowed spastic fashion, quite different from Parkinson disease, the mouth tends to be held open, and swallowing is difficult. Many patients complain of sleep disturbances. The total sleep time and REM sleep are reduced, and spontaneous awakenings during the night are more frequent and longer than in normal individuals of the same age. Complaints of


Neurology_Adams

Neurology_Adams. sleep disturbances. The total sleep time and REM sleep are reduced, and spontaneous awakenings during the night are more frequent and longer than in normal individuals of the same age. Complaints of urinary frequency and urgency have also been frequent in advanced cases under our care. Dubois and colleagues proposed an “applause sign” as distinctive to this disease; the patient fails to stop clapping after being asked to do so only 3 times.


Neurology_Adams

Neurology_Adams. The diagnosis often proves difficult to make if the main ocular features are not outstanding. Other features, such as tremor, palilalia, myoclonus, chorea, orofacial dyskinesias, and disturbances of vestibular function, are observed in some cases. Finally the patient becomes anarthric, immobile, and quite helpless. Dementia of some degree is probably present in many cases, but is mild in most. Some patients do become forgetful and appear apathetic and slow in thinking; many others are irritable or at times euphoric.


Neurology_Adams

Neurology_Adams. By MRI one can, in advanced cases, appreciate atrophy of the dorsal mesencephalon (superior colliculi, red nuclei) giving rise to a “mouse ears” configuration (Fig. 38-7A), but these changes may not be evident early in the illness when diagnosis is most difficult. Several measurements of midbrain atrophy have been proposed as aiding diagnosis; for example, there is little overlap between PSP, multiple system atrophy, and Parkinson disease in the ratio of midbrain-to-pons cross-sagittal area, according to Oba and colleagues. The apparent selective atrophy of the dorsal midbrain on mid-sagittal images has been referred to as the “hummingbird sign” (Fig. 38-7B). However, midbrain atrophy must be judged in the context of global brain atrophy (and of the symptoms) in an individual patient. The CSF remains normal. Nonetheless, the diagnosis continues to rest on the clinical features, mainly affecting eye movements.


Neurology_Adams

Neurology_Adams. Pathology Postmortem examinations have disclosed a bilateral loss of neurons and gliosis in the periaqueductal gray matter, superior colliculus, subthalamic nucleus, red nucleus, pallidum, dentate nucleus, and pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus. The expected loss of the myelinated fiber bundles arising from these nuclear structures has also been commented upon. The remarkable finding has been the neurofibrillary degeneration of many of the residual neurons. The neurofibrillary tangles are thick and often composed of single strands, either twisted or in parallel arrangement. The neurons of the cerebral cortex have been involved in some cases (shown by staining of tau protein), but these changes do not correlate with dementia. The cerebellar cortex is usually spared.


Neurology_Adams

Neurology_Adams. The cause and nature of this disease remain obscure. Though some clinical and pathologic heterogeneity is seen, the majority of cases of PSP conform to the typical pattern as we have just described. These interesting diagnostic and clinicopathologic aspects are summarized by Williams and Lees. Studies with PET demonstrate a decrease in blood flow, most marked in the frontal lobes, and a lesser extent of oxygen utilization in central structures (Leenders et al). Striatal dopamine formation and storage are significantly decreased when compared with control values. Much current interest has been directed to the neurofibrillary tangles and tau deposition in PSP and a potential link to the tau pathology displayed in frontotemporal dementia and in corticobasalganglionic degeneration (see in the following text). Certain tau gene (MAPT) haplotypes on chromosome 17p (the same site implicated in familial frontotemporal dementia) are more often associated with PSP than in unaffected individuals.


Neurology_Adams

Neurology_Adams. following text). Certain tau gene (MAPT) haplotypes on chromosome 17p (the same site implicated in familial frontotemporal dementia) are more often associated with PSP than in unaffected individuals. A recent investigation into the mechanism of postural instability using functional imaging, showed a correlation between gait instability and decreased thalamic glucose metabolism and activation (Zwergal).


Neurology_Adams

Neurology_Adams. PSP should be suspected whenever an older adult inexplicably develops a state of imbalance, frequent falls with preserved consciousness, and variable extrapyramidal symptoms, particularly dystonia of the neck, ocular palsies, or a picture resembling pseudobulbar palsy. If the typical abnormalities of eye movements are present, the diagnosis is not difficult. When only a parkinsonian syndrome without tremor is apparent the main diagnostic consideration is striatonigral degeneration or the corticobasalganglionic syndrome, described below.


Neurology_Adams

Neurology_Adams. Treatment l-Dopa has been of slight and unsustained benefit in some of our patients, and combinations of l-dopa and anticholinergic drugs have been entirely ineffective in others. A marked response to these drugs should, of course, suggest the diagnosis of Parkinson disease. Recently, the drug zolpidem, a gabanergic agonist of benzodiazepine receptors, has been reported to ameliorate the akinesia and rigidity of PSP (Daniele et al); however, these observations require corroboration. Benztropine or trihexyphenidyl has been somewhat helpful in reducing dystonia but botulinum injections may be a better alternative if there are focal signs. Treatments of the sleep difficulties and urinary incontinence are of great assistance to the patient and family. A feeding tube becomes necessary in advanced cases. Observing the decline of these patients and the limitations of treatment is a frustrating ordeal for all involved.


Neurology_Adams

Neurology_Adams. Most neurologists have observed elderly patients in whom the essential abnormality was a progressive asymmetrical extrapyramidal rigidity combined with signs of corticospinal disease. Sometimes a mild postural action tremor beginning unilaterally and suggestive in some respects of Parkinson disease has been added. The parkinsonism is generally unresponsive to l-dopa. These cases have come to be known by the names corticobasal-ganglionic or cortical-basal degeneration and like sounding terms. The relation of such cases to corticostriatospinal degeneration described further on and to frontotemporal lobar degeneration and to progressive supranuclear palsy, is unified by the finding of tau inclusions.


Neurology_Adams

Neurology_Adams. Wenning and colleagues (1994) described a series of such patients in whom the diagnosis was confirmed at postmortem examination. The most common early symptom was an asymmetrical clumsiness of the limbs in half of the patients, with rigidity and, in one-fifth, with tremor; these features are now considered to be the most characteristic early features of the process. As the illness progressed, almost all the patients developed an asymmetric or unilateral akinetic-rigid syndrome, which may be considered the essential motor disorder of this disease, and various forms of gait disorder and dysarthria. Stimulus-induced or spontaneous myoclonus and pyramidal signs, mentioned in other reports and frequent in our cases, were not prominent in their series; limitations of vertical gaze and frontal lobe release signs eventually became apparent in half.


Neurology_Adams

Neurology_Adams. Eventually, although able to exert considerable muscle power, these patients cannot effectively direct their voluntary actions. Attempts to move a limb to accomplish some purposeful act might result in a totally inappropriate movement, always with great enhancement of rigidity in the limb and in other affected parts, or the limb may drift off and assume an odd posture, such as a persistent elevation of the arm without the patient’s awareness—a kind of catalepsy. The disorder of limb function has some of the attributes of a limb-kinetic or an ideomotor apraxia (see Chap. 3), but the hand postures, involuntary movements, and changes in tone are at times more of the type described as “alien hand.” Some patients exhibit anosognosia, Babinski signs, impaired eyelid or ocular motion (upgaze paresis or abnormal saccadic movements), lingual dyskinesias, frontal release signs, myoclonus, or dysarthria.


Neurology_Adams

Neurology_Adams. Babinski signs, impaired eyelid or ocular motion (upgaze paresis or abnormal saccadic movements), lingual dyskinesias, frontal release signs, myoclonus, or dysarthria. Another distinct group has dementia as an early feature, as described by Grimes and colleagues, but mental deterioration is more often late and may not occur in all patients. There are also rare patients who present with behavioral disturbance or nonfluent aphasias as early features, which are difficult to distinguish from subtypes of frontotemporal dementia (Lee and colleagues, 2011). Occasionally, there is some involvement of lower motor neurons with resulting amyotrophy. Several of our patients had myoclonus as an early feature, one displaying it only on one side of the face, the other in an arm. The condition progresses for 5 years or more before some medical complication overtakes the patient.


Neurology_Adams

Neurology_Adams. Postmortem examination of patients, originally reported by Rebeiz and colleagues, disclosed a combination of findings that differentiated the disease process from other neurodegenerative conditions. Cortical atrophy (mainly in the frontal motor–premotor and anterior parietal lobes) was associated with degeneration of the substantia nigra and, in one instance, of the dentatorubrothalamic fibers. The loss of nerve cells was fairly marked, but there was no gross lobar atrophy, as occurs in Pick disease. The neuronal degeneration was more on one side of the brain than the other. There was moderate gliosis in the cortex and underlying white matter. The disease is now clearly considered to be related to tau deposition in specific brain structures; however, the original authors were more impressed with ballooned and chromatolytic neurons with eccentric nuclei, a state that was called neuronal achromasia. The presence of these achromatic cells in posterior frontal and parietal neurons


Neurology_Adams

Neurology_Adams. impressed with ballooned and chromatolytic neurons with eccentric nuclei, a state that was called neuronal achromasia. The presence of these achromatic cells in posterior frontal and parietal neurons continues to be considered an essential feature of the disease, although the rounded areas within neurons stain for tau and resemble globose tangles that are found occasionally in Alzheimer disease (corticobasal bodies); in this way, CBGD is connected to the other tau-related neurodegenerative diseases, or “tauopathies.” In addition, adjacent glia are filled with various configurations of tau protein, thereby linking the disease to frontotemporal lobar degeneration and PSP. Our colleague Feany, with Dickson, has identified one type of these as “plaques” in the cortex that are composed of tau aggregates within the distal processes of astrocytes.


Neurology_Adams

Neurology_Adams. Both CT and MRI have demonstrated asymmetrical cerebral and pontine atrophy, and PET studies have revealed thalamoparietal metabolic asymmetries—a greater reduction of glucose metabolism on the side of the most extensive lesion (Riley et al). There are no clues as to the pathogenesis of this disease. There are rare familial types but no definite genetic cause has been identified. No organ other than the CNS is affected. The progression is relentless. None of the drugs in common use for spasticity, rigidity, and tremor has been helpful. Included in this category are a heterogeneous group of degenerative diseases in which the symptoms of parkinsonism and corticospinal degeneration are present in various combinations. Some of the diseases that make up this group have not been sharply delineated and are difficult to separate from one another. Moreover, the relationship of this process to the better defined corticobasal degeneration, explained above, is indeterminate.


Neurology_Adams

Neurology_Adams. Under the title “Spastic Pseudosclerosis,” Jakob, in 1921, described a chronic disease of middle to late adult life, characterized by abnormalities of behavior and intellect; weakness, ataxia, and spasticity of the limbs (chiefly the legs); extrapyramidal symptoms such as rigidity, slowness of movement, tremors, athetotic postures, and hesitant, dysarthric speech; and normal spinal fluid. The pathologic changes were diffuse and consisted mainly of an outfall of neurons in the frontal, temporal, and central motor gyri, striatum, ventromedial thalamus, and bulbar motor nuclei. In one of Jakob’s cases, there were also prominent changes in the anterior horn cells and corticospinal tracts in the spinal cord like those of ALS. The latter finding gave rise to Wilson’s concept of the disease as a corticostriatospinal degeneration. Some restricted cases bear a resemblance to the type of frontotemporal dementia that occurs with motor neuron disease.


Neurology_Adams

Neurology_Adams. Variants of this category of disease continue to appear, all rare. The authors have observed several patients in whom extreme rigidity, corticospinal signs but no dementia, have developed over a period of several years. In the later stages of the disease, the patient, while alert, is totally helpless and unable to speak, swallow, or move the limbs. Only eye movements are retained, and even these are hampered by supranuclear gaze palsies in advanced cases. Intellectual functioning at this stage appears to be better preserved than movement but is difficult to assess. Other bodily functions are intact. The course is slowly progressive and ends fatally in 5 to 10 years. There is no family history of similar disease, and there are no clues as to causation. Gilbert and colleagues have described similar cases with signs of Parkinson disease, motor neuron disease, and dementia; in their cases, there were no senile plaques or Lewy bodies. The concurrence of typical motor neuron disease and


Neurology_Adams

Neurology_Adams. similar cases with signs of Parkinson disease, motor neuron disease, and dementia; in their cases, there were no senile plaques or Lewy bodies. The concurrence of typical motor neuron disease and Parkinson disease may be coincidental, but Qureshi and colleagues described 13 patients in whom both clinical phenomena began within a short time and they considered them to be related. In the variant described by


Neurology_Adams

Neurology_Adams. Tandan and colleagues, an autosomal dominant syndrome of Charcot-Marie-Tooth polyneuropathy was combined with ptosis, parkinsonism, and dementia, again without Lewy bodies or amyloid plaques. Other variants have been described by Schmitt and coworkers and by Mata and colleagues. Hudson reviewed 42 sporadic cases in which ALS-parkinsonism-dementia were combined.


Neurology_Adams

Neurology_Adams. A degenerative and probably familial disorder that had been described earlier by Creutzfeldt was considered by Spielmeyer to be sufficiently similar to the one of Jakob to warrant the designation Creutzfeldt-Jakob disease. As discussed in Chap. 32, the disorder originally described by Creutzfeldt and Jakob has been a source of endless controversy because of its indeterminate character. It has been confused with the subacutely evolving myoclonic dementia, or subacute spongiform encephalopathy, which is now known to be an infection caused by a prion agent. The latter disease bears at best only a superficial resemblance to the one described by Creutzfeldt and Jakob, and the 2 disorders should be separated. Unfortunately, the use of the eponym for the prion-related disease is so entrenched that attempts to delete it are futile and probably unnecessary. However, the term Jakob disease has been used for the degenerative type of corticostriatospinal degeneration.


Neurology_Adams

Neurology_Adams. The Guamanian Parkinson-dementia-ALS complex deserves separate comment because there have been many carefully studied cases with almost uniform clinical and pathologic features. The disease occurs in the indigenous Chamorro peoples of Guam and the Mariana islands, predominantly in men between the ages of 50 and 60 years. Progressive parkinsonism and dementia are combined with upper or lower motor neuron disease (ALS is also common among the Chamorro) leading to death in 5 years. The pathologic changes, described by Hirano and associates, consist of severe cortical atrophy with neurofibrillary tangles and a depopulation of the substantia nigra, but notably no Lewy bodies or amyloid plaques, even with sensitive neurochemical staining. Cases with amyotrophy show a loss of anterior horn cells. The cause of the Guamanian multisystem degeneration is not known, although several studies have incriminated one or more putative neurotoxins in the food supply (see Chap. 41). There are some


Neurology_Adams

Neurology_Adams. cells. The cause of the Guamanian multisystem degeneration is not known, although several studies have incriminated one or more putative neurotoxins in the food supply (see Chap. 41). There are some clinical and pathologic similarities to the form of frontotemporal dementia with motor neuron disease.


Neurology_Adams

Neurology_Adams. There are 2 categories of neurologic disease associated with red blood cell acanthocytosis; one with a defect in the red cell lipid membrane (consisting of Bassen-Kornzweig disease and the disorder called HARP [hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration] syndrome [see Chap. 36]); and a second group that lacks a lipid abnormality. The main syndrome, and the one to which the term neuroacanthocytosis had for a long time been applied, is caused by an autosomal recessive mutation. However, there are now 4 additional subtypes, one dominantly transmitted and another X-linked (McLeod type), which is discussed below. These are all in distinction to Bassen-Kornzweig disease that is caused by a defect in the lipid layer of the red cell membrane that leads to the red cell deformity (see further on).


Neurology_Adams

Neurology_Adams. In the series of 19 cases of typical neuroacanthocytosis reported by Hardie and colleagues, the manifestations included dystonia, tics, vocalizations, rigidity, and lip and tongue biting; more than half had cognitive impairment or psychiatric features. The average age of onset was 32 years; 7 of the 19 cases were sporadic. The disease has been linked in almost all families to chromosome 9q, where there is a mutation in the gene encoding a large (3,100-amino-acid) protein designated chorein that is involved in cellular protein sorting and trafficking (Rampoldi). Some of the families with dominantly inherited neuroacanthocytosis have mutations in the chorein gene. There is atrophy and gliosis of the caudate nuclei and putamens but no neuronal loss in the cerebral cortex or other parts of the brain.


Neurology_Adams

Neurology_Adams. According to Sakai and coworkers (1991), the acanthocytosis is the result of an abnormal composition of covalently (tightly) bound fatty acids in erythrocyte membrane proteins (palmitic and docosahexaenoic acids increased and stearic acid decreased). The red cells should be examined in a fresh preparation of blood in isotonic saline; it is likely to be overlooked in a conventional Wright stain from a hospital laboratory. More than 5 percent of the red cells have the characteristic structural abnormality in affected individuals. The acanthocytosis may also be detected by scanning electron microscopy. The latter may be necessary to undertake in cases of unexplained chorea that have the other features of this disease as genetic testing for the gene (see in the following text) is not widely available.


Neurology_Adams

Neurology_Adams. The second less common category of neuroacanthocytosis enters into the differential diagnosis of Huntington chorea or unexplained progressive choreas and has the following characteristics: (1) onset in adolescence or early adult life of generalized involuntary movements (described as chorea but including dystonia and tics), usually beginning as an orofacial dyskinesia and spreading to other parts of the body and to other neural systems; (2) mild to moderate mental deterioration with behavioral disturbance in some but not all cases; (3) decreased or absent tendon reflexes and evidence of chronic axonal neuropathy and denervation atrophy of muscles; and (4) the defining feature of acanthocytosis (thorny or spiky appearance of erythrocytes).


Neurology_Adams

Neurology_Adams. McLeod disease, another disorder with acanthocytosis and the gradual development of chorea in middle to late life, is characterized by degeneration of the caudate and putamen and a myopathy (elevated serum creatine phosphokinase [CPK]). These individuals have fewer facial tics and orofacial features than those with neuroacanthocytosis. McLeod syndrome arises from mutations in a gene on the X-chromosome that encodes the KX protein, which binds to surface Kell antigens on red cells. In addition to the primary KX gene mutations, these individuals show diminished Kell antigen expression on the red-cell surface.


Neurology_Adams

Neurology_Adams. Dystonia as a symptom was discussed in Chaps. 3 and 4. Here we are concerned with a disease or diseases of which dystonia is the major manifestation. The broad category of primary dystonias and what has been termed “dystonia-plus,” meaning the addition of features such as parkinsonism or tremor, are now denominated by “DYT” followed by a number. It is more practical to know the gene correlate of each clinical disorder. The most important of these is DYT1, or dystonia musculorum deformans.


Neurology_Adams

Neurology_Adams. Historical aspects Schwalbe’s account, in 1908, of 3 siblings of a Jewish family who were afflicted with progressive involuntary movements of trunk and limbs probably represents the first description of a disease in which severe and progressive dystonia was the sole manifestation. In 1911, Oppenheim contributed other cases and coined the term dystonia musculorum deformans in the mistaken belief that the disorder was primarily one of muscle and always associated with deformity. Flatau and Sterling, in the same year, first suggested that the disease might have a hereditary basis and gave it the more accurate name torsion dystonia of childhood. At first, the condition was considered by some to be a manifestation of hysteria; only later was it recognized as a neurologic entity with a predilection for individuals of Eastern European Jewish origin. Soon thereafter, a second hereditary form of torsion dystonia, affecting non-Jews, was observed. The recessive form begins in early childhood,


Neurology_Adams

Neurology_Adams. for individuals of Eastern European Jewish origin. Soon thereafter, a second hereditary form of torsion dystonia, affecting non-Jews, was observed. The recessive form begins in early childhood, is progressive over a few years, and is restricted to Jewish patients. The dominant form begins later, usually in late childhood and adolescence, progresses more slowly, and is not limited to any ethnic group.


Neurology_Adams

Neurology_Adams. As indicated in Chap. 4, most instances of idiopathic (primary) dystonias that come to our attention, particularly the segmental or restricted types, do not conform to the typical hereditary disorder as defined above, although some may represent limited variants of the inherited form of disease. In general, the more restricted types have a later onset and a relatively milder, more slowly progressive course, with a tendency to involve an axial or a distal region alone. Only the paravertebral, cervical, or cranial muscles may be involved (focal dystonia including torticollis and writer’s cramp), with little change from year to year. The clinical classification of the predominantly adult-onset dystonias is made more complex by the fact that both the restricted and generalized forms may be sporadic or genetic.


Neurology_Adams

Neurology_Adams. Genetic aspects Molecular genetic studies, although still incomplete, hold the promise of clarifying the classification of the heritable dystonias. Six genes have been identified as causing primary dystonias and a number of others cause what might called “dystonia-plus” as they encompass tremor, parkinsonism or myoclonus. The most important of these is an abnormal gene (DYT1, also known as TOR1A) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families. The most common mutation in DYT1 is a deletion of a single glutamate from the torsin A peptide and accounts for most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene.


Neurology_Adams

Neurology_Adams. The function of torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Walker and Shashidharan).


Neurology_Adams

Neurology_Adams. Although DYT1 mutations account for the majority of inherited cases of generalized dystonia, they are also implicated in a small proportion of the more restricted dystonias, particularly blepharospasm (see further on). Some individuals in families affected with generalized dystonia will demonstrate only localized forms (e.g., writer’s cramp or torticollis). The general rule stated above still holds, namely, that the inherited variety (dystonia musculorum deformans) related to DYT1 manifests early in life and begins in one limb and then spreads to most muscles of the body, while in the common dystonias (mostly sporadic but some heritable) the disease remains confined to the craniocervical or another region, does not generalize, and has an adult onset.


Neurology_Adams

Neurology_Adams. Clinical features The first manifestations of the generalized disease may be rather subtle. Intermittently, and usually after activity (late in the day), the patient (usually a child between 6 and 14 years of age, less often an adolescent) begins to invert one foot, to extend one leg and foot in an unnatural way, or to hunch one shoulder, raising the question of a nervous tic. As time passes, the motor disturbance becomes more persistent and interferes increasingly with the patient’s activities. Soon the muscles of the spine and shoulder or pelvic girdle become implicated in involuntary spasmodic twisting movements. The cardinal feature of these severe dystonic muscle contractions is the simultaneous contraction of both agonists and antagonists at a joint. These cocontraction spasms are intermittent at first; in intervals that are free of the dystonia, muscular tone and volitional movements are normal. In some instances, the muscles are hypotonic. Gradually, the spasms become more


Neurology_Adams

Neurology_Adams. intermittent at first; in intervals that are free of the dystonia, muscular tone and volitional movements are normal. In some instances, the muscles are hypotonic. Gradually, the spasms become more frequent; finally, they are continuous and the body may become grotesquely contorted, as shown in Fig. 4-5A. Lateral and rotatory scoliosis uniformly results as secondary deformities. For a time, recumbency relieves the spasms, but later on position has no influence. The hands are seldom involved, although at times they may be held in a fisted posture. Cranial muscles do not escape, and in a few instances a slurring, staccato-type speech was the initial manifestation. Uncontrollable blepharospasm was the initial disorder in one of our patients; in two others, severe dysarthria and dysphagia were the first signs, caused by dystonia of the tongue, pharyngeal, and laryngeal muscles.


Neurology_Adams

Neurology_Adams. Other manifestations include torticollis, tortipelvis, dromedary gait, propulsive gait, action tremor, myoclonic jerks during voluntary movement, and mild choreoathetosis of the limbs. Excitement worsens the dystonia and sleep abolishes it. As the years pass the postural distortion may become fixed to the point where it does not disappear even in sleep. Tendon reflexes are normal, corticospinal signs are absent, and there is no ataxia, sensory abnormality, convulsive disorder, or dementia.


Neurology_Adams

Neurology_Adams. Pathology No agreement has been reached concerning the pathologic substrate of the disease. None of the features of symptomatic dystonia are found, such as the ferrocalcinosis of PKAN, the lesions of Wilson disease, kernicterus, état marbré of neonatal hypoxia, or the cavitation of familial striatal necrosis. However, in the hereditary forms of dystonia, which are the subject of this section, one cannot be certain of any specific lesions that would account for the clinical manifestations. The brain is grossly normal and ventricular size is not increased. According to Zeman, who reviewed all the reported autopsy studies up to 1970, there were no significant changes in the striatum, pallidum, or elsewhere. This means only that the techniques being used (qualitative analysis of random sections by light microscopy) are inadequate or the problem is subcellular. The report by McNaught and colleagues of perinuclear inclusions in periaqueductal neurons by the use of special immunostaining


Neurology_Adams

Neurology_Adams. by light microscopy) are inadequate or the problem is subcellular. The report by McNaught and colleagues of perinuclear inclusions in periaqueductal neurons by the use of special immunostaining methods is provocative. There had been tentative interest in elevations of dopamine β-hydroxylase in patients with the autosomal dominant form of the disease, but the meaning of these findings is not clear.


Neurology_Adams

Neurology_Adams. Treatment Early in the course of the illness, several drugs including l-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism (described below) responds well to small doses of l-dopa and dopamine agonists and is exceptional in this respect. Burke and coworkers advocate the use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus.


Neurology_Adams

Neurology_Adams. Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. Approximately 70 percent of the patients in Cooper’s series in the 1950s were moderately to markedly improved by unilateral or bilateral operations and, based on a 20-year followup study, the improvement was usually sustained. More recent studies report a somewhat less favorable but nonetheless clear improvement (see Tasker et al; Andrew et al, de Bie et al). The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over longer periods, by bilateral stimulation of the internal segments of the globus


Neurology_Adams

Neurology_Adams. sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over longer periods, by bilateral stimulation of the internal segments of the globus pallidus (Vidailhet and colleagues).


Neurology_Adams

Neurology_Adams. Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia, GCH1 Mutation)


Neurology_Adams

Neurology_Adams. This process is discussed here because its main characteristic is a dystonia that is responsive to l-dopa, but most cases also have features of parkinsonism, which is why it was also mentioned in the earlier discussion of hereditary forms of Parkinson disease, especially in young patients. Following the description of the syndrome by Segawa and colleagues in 1976, others drew attention to this unique form of hereditary dystonia (Allen and Knopp; Deonna; Nygaard and Duvoisin). The pattern of inheritance is autosomal dominant and there is no ethnic predilection. Nygaard and colleagues found a linkage to the gene on chromosome 14q for the protein GTP cyclohydrolase 1 (GCH1 gene) that is implicated in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. It is likely that the mutation impairs the generation of dopamine, a prediction that accords with responsiveness of the parkinsonian and dystonic features to l-dopa. In one autopsied case (an accidental death), there


Neurology_Adams

Neurology_Adams. the mutation impairs the generation of dopamine, a prediction that accords with responsiveness of the parkinsonian and dystonic features to l-dopa. In one autopsied case (an accidental death), there was a reduction in the amount of tyrosine hydroxylase in the striatum and depigmentation but no cell loss in the substantia nigra (Rajput et al). The affected enzyme was reduced in the striatum, as was the level of dopamine.


Neurology_Adams

Neurology_Adams. The dystonic manifestations usually become evident in childhood, usually between 4 and 8 years of age; females outnumber males in a ratio of 3:2. Often the legs are first affected by intermittent stiffening, with frequent falls and peculiar posturing, sometimes the feet assuming an equinovarus position. The arms become involved as well as the truncal muscles; retrocollis or torticollis may appear. Within 4 to 5 years, all parts of the body, including the bulbar muscles, are involved. Mild parkinsonian features (rigidity, bradykinesia, postural instability) can usually be detected early in the course of the illness, but more characteristically they are added to the clinical picture several years later. In our own patients, and in several of those of Deonna, there was rigidity of the limbs as well as slowness of movement and a tremor at rest, all aspects more parkinsonian than dystonic. In still others, the clinical picture has been one of cerebral spastic diplegia.


Neurology_Adams

Neurology_Adams. The special feature of this juvenile dystonia-parkinsonism syndrome is the dramatic response of both the dystonic and parkinsonian symptoms to treatment with l-dopa. As little as 20-200 mg/d may eliminate the movement disorder and permit normal functioning. Unlike idiopathic Parkinson disease, the medication can be continued indefinitely without the development of tolerance, wearing-off effects, or dyskinesias. Segawa disease accounts for some cases that had in the past been reported as juvenile Parkinson disease. Another feature is the disappearance or marked subsidence of the symptoms after a period of sleep and worsening as the day progresses. This diurnal variation is shared with many of the inherited (and sporadic) forms of Parkinson disease listed in Table 38-3. Fluctuations of symptoms with exercise and menses and in the first month of pregnancy have been observed in some cases. Torticollis and Other Restricted Dyskinesias and Dystonias (See Chap. 4)


Neurology_Adams

Neurology_Adams. Torticollis and Other Restricted Dyskinesias and Dystonias (See Chap. 4) With advancing age, a large variety of focal or regional movement disorders come to light. Various neurophysiologic abnormalities, summarized in Chap. 4, have been implicated. In the common restricted dystonias, localized groups of adjacent muscles manifest arrhythmic cocontracting spasms (i.e., agonist and antagonist muscles are activated simultaneously). The patient’s inability to suppress the dystonia and the recognition that it is for the most part beyond voluntary control distinguishes it from tics, habit spasms, and mannerisms described in


Neurology_Adams

Neurology_Adams. Chap. 4. If the muscle contraction is frequent and prolonged, it is accompanied by an aching pain that may mistakenly be blamed for the spasm and the involved muscles may gradually undergo hypertrophy. Worsening under conditions of excitement and stress and improvement during quiet and relaxation are typical of this group of disorders and contributed in the past to the mistaken notion that the spasms had a psychogenic origin.


Neurology_Adams

Neurology_Adams. The most frequent and familiar type is torticollis, wherein an adult, more often a woman, becomes aware of a turning of the head to one side while walking. Usually this condition worsens gradually to a point where it may be more or less continuous, but in some patients it remains mild or intermittent for years on end. When followed over the years, the condition is observed to remain limited to the same muscles (mainly the scalene, sternocleidomastoid, and upper trapezius). Rarely, the torticollis is combined with dystonia of the shoulder, arm, and trunk; tremor; facial spasms; or dystonic writer’s cramp.


Neurology_Adams

Neurology_Adams. Other restricted dyskinesias involve the neck in combination with facial muscles, the orbicularis oculi (blepharospasm and blepharoclonus), the throat and respiratory muscles (spastic dysphonia, orofacial dyskinesia, and respiratory and phonatory spasms), the hand in writer’s cramp (graphospasm) or musician and other performing artist’s dystonia, and proximal leg and pelvic-girdle muscles, where dyskinesia is elicited by walking. All these conditions and their treatments are discussed fully in Chap. 4. Other Forms of Hereditary Dystonia


Neurology_Adams

Neurology_Adams. Other Forms of Hereditary Dystonia Several familial movement-induced (kinesogenic) dystonic syndromes and a type that is not kinesogenic and arises suddenly in adolescence, at times with parkinsonian features, have been described. There are other degenerative diseases that combine hereditary dystonia with neural deafness and intellectual impairment (Scribanu and Kennedy) and with amyotrophy in a paraplegic distribution (Gilman and Romanul). These are discussed in greater detail in Chap. 4 and have assignments using the DYT nomenclature. The mutations causing the dystonias are distributed throughout the genome and have both dominant and fewer, recessive or X-linked, patterns of inheritance.


Neurology_Adams

Neurology_Adams. Other important symptomatic dystonias that fall into the category of hereditary dystonia were described in Chap. 36. These are PKAN and calcification of the basal ganglia; of course, Wilson disease may also have dystonia as a central feature. Many extrapyramidal diseases, including idiopathic Parkinson disease and progressive supranuclear palsy, may include fragmentary dystonias of the hand, foot, face, or periorbital muscles.


Neurology_Adams

Neurology_Adams. Wilson wrote that “the group of degenerative conditions strung together by the common feature of ataxia is one for which no very suitable classification has yet been devised,” a statement that is not as appropriate today as when it was written 80 years ago. This topic was introduced in Chap. 5 and some of the congenital and acute acquired varieties are mentioned there. Here we consider the chronic, progressive forms of cerebellar disease. Although most of these are familial and are more or less confined to this part of the nervous system, a number of other systems may be involved to varying degrees. Most of the chronic progressive cerebellar diseases are subsumed under the “system atrophies,” but no one classification designed to bring order to this category of diseases has proved satisfactory and a preferable genetic classification is emerging.


Neurology_Adams

Neurology_Adams. Setting aside those of congenital type and those caused by a metabolic disorder, Harding (1993) grouped the ataxias by age of onset, pattern of heredity, and associated features. A modification of the classifications of Greenfield and of Harding, which is included in the introductory listing of this chapter, still has clinical value. It divides the progressive cerebellar syndromes into 3 main groups: (1) the spinocerebellar ataxias, with unmistakable involvement of the spinal cord (Romberg sign, sensory loss, diminished tendon reflexes, Babinski signs); (2) the pure cerebellar ataxias, with no other associated neurologic disorders; and (3) the complicated cerebellar ataxias, with a variety of pyramidal, extrapyramidal, retinal, optic nerve, oculomotor, auditory, peripheral nerve, and cerebrocortical accompaniments including what is now referred to as multiple system atrophy.


Neurology_Adams

Neurology_Adams. Without doubt, the advances in molecular genetics of recent years have greatly altered our understanding of the inherited ataxias and have already disclosed a large number of unexpected relationships between mutations and other neural and nonneural disorders. These data are incorporated at appropriate points in the following discussion and in Table 38-5. Inherited ataxias of early onset (before the age of 20 years) are usually of recessive type; those of later onset are more likely to have a dominant pattern but may be autosomal recessive. Table 38-5 lists several types of ataxias that have a genetic basis. At the time of this writing, many more types have been listed in the literature, most of limited clinical consequence and low incidence. We have included the main varieties that may be of interest to clinicians because they appear regularly or offer an insight into this class of disorders. At the same time, it should be emphasized that many patients with chronic progressive ataxia


Neurology_Adams

Neurology_Adams. of interest to clinicians because they appear regularly or offer an insight into this class of disorders. At the same time, it should be emphasized that many patients with chronic progressive ataxia have no family history of an ataxia and may have had a spontaneous mutation; even then, the genetic aspects of many cases have not been elucidated.


Neurology_Adams

Neurology_Adams. This is the prototype of all forms of progressive spinocerebellar ataxias (ataxias with signs of predominantly spinal tract degeneration) and accounts for about half of all cases of hereditary ataxias in most large case series (86 of 171 patients collected by Sjögren); its incidence among


Neurology_Adams

Neurology_Adams. Europeans and North Americans is 1.5 cases per 100,000 per year. Friedreich, of Heidelberg, began in 1861 to report on a form of familial progressive ataxia that he had observed among nearby villagers. It was already known through the writings of Duchenne that locomotor ataxia was the prominent feature of spinal cord syphilis, that is tabes dorsalis, but it was Friedreich who demonstrated a nonsyphilitic hereditary type. This concept was greeted with skepticism, but soon Duchenne himself affirmed the existence of the new disease and other case reports appeared in England, France, and the United States. In 1882, in a thesis on this subject by Brousse of Montpelier, Friedreich’s name was attached to the entity.


Neurology_Adams

Neurology_Adams. The pattern of inheritance is autosomal recessive. It has been shown that in virtually all cases the mutation is an expansion of a GAA trinucleotide repeat within FXN that that codes for the protein. (It is of interest that this mutation is within an intron). In a small proportion of cases, the mutation is a missense mutation rather than an expansion. In either case, the consequence of the mutation is a reduction in levels of frataxin and loss of its function. Cases in which the mutation allows the presence of some residual protein have a milder course.


Neurology_Adams

Neurology_Adams. The GAA expansion is found on both alleles in intron 1 (non-coding) of the frataxin gene in a majority of patients. A number of mechanisms have been put forward to explain the loss of function caused by this mutation. The length of the GAA expansion has been shown to correlate with disease severity and symptom onset; the length of the shorter of the 2 expansions being the most important predictor. Reduced mRNA production has been suggested to occur through abnormal silencing of the gene via epigenetic mechanisms. This may be a potential target for treatment (see in the following text). Aberrant DNA methylation, histone methylation, antisense transcription and secondary structure formation have been shown to be involved in the pathological silencing of this gene.


Neurology_Adams

Neurology_Adams. Clinical features Ataxia of gait is nearly always the initial symptom. Difficulties in standing steadily and in running are early symptoms. The typical age of onset is in the childhood and adolescent period. The hands usually become clumsy months or years after the gait disorder, and dysarthric speech appears after the arms are involved (this is rarely an early symptom). Exceptionally, the ataxia begins rather abruptly after a febrile illness, and one leg may become clumsy before the other. In some patients, pes cavus and kyphoscoliosis (scoliosis) are evident well before the neurologic symptoms; in others, they follow by several years. The characteristic foot deformity takes the form of a high plantar arch with retraction of the toes at the metatarsophalangeal joints and flexion at the interphalangeal joints (hammertoes).


Neurology_Adams

Neurology_Adams. In the fully developed syndrome, the abnormality of gait is of mixed sensory and cerebellar type, aptly called tabetocerebellar by Charcot. According to Mollaret, the author of an authoritative monograph on the disease, the cerebellar component predominates, but in our relatively small experience we have been as impressed almost as much with the sensory (tabetic) aspect. The patient stands with feet wide apart, constantly shifting position to maintain balance. Friedreich referred to the constant teetering and swaying on standing as static ataxia. In walking, as with all sensory ataxias, the movements of the legs tend to be brusque, the feet resounding unevenly and irregularly as they strike the floor, and closure of the eyes causes the patient to fall (Romberg sign). This is one component of the spinal aspect (posterior columns) of the disease. Attempts to correct the imbalance may result in abrupt, wild movements. Often there is a rhythmic tremor of the head. Eventually, the arms are


Neurology_Adams

Neurology_Adams. of the spinal aspect (posterior columns) of the disease. Attempts to correct the imbalance may result in abrupt, wild movements. Often there is a rhythmic tremor of the head. Eventually, the arms are grossly ataxic, and both action and intention tremors are manifest. Speech is slow, slurred, explosive, and, finally, almost incomprehensible. Breathing, speaking, swallowing, and laughing may be so incoordinated that the patient nearly chokes while speaking. Holmes (1907a) remarked on an ataxia of respiration that causes “curious short inspiratory whoops.” Facial, buccal, and arm muscles may display tremulous and sometimes choreiform movements.


Neurology_Adams

Neurology_Adams. Although mentation is generally preserved, emotional lability has been sufficiently prominent to provoke comment. Torsional and vertical nystagmus is rare but “square wave jerks” are seen in the early stages of disease. Horizontal nystagmus may be present late in the course of the illness, but not early, but it is slight in amplitude. Ocular movements usually remain full, and pupillary reflexes are normal. The facial muscles may seem slightly weak, and deglutition may become impaired. Amyotrophy occurs late in the illness and is usually mild, but it may be extreme in patients with an associated neuropathy (see in the following text).


Neurology_Adams

Neurology_Adams. The tendon reflexes are abolished in nearly every case; rarely, they may be obtainable when the patient is examined early in the illness (see in the following text). Plantar reflexes are extensor and flexor spasms may occur even with complete absence of tendon reflexes (another manifestation of the spinal component). The abdominal reflexes are usually retained until late in the illness. Loss of vibratory and position sense is invariable from the beginning; later, there may be some diminution of tactile, pain, and temperature sensation as well. Sphincter control is usually preserved.


Neurology_Adams

Neurology_Adams. A notable feature in more than half of patients is a cardiomyopathy. The myocardial fibers are hypertrophic and may contain iron-reactive granules (Koeppen). Many of the patients die as a result of cardiac arrhythmia or congestive heart failure. For this reason, it is essential that affected individuals have a cardiologic assessment including electrocardiography and echocardiography. The cardiomyopathy of Friedreich disease can develop insidiously but with fulminant consequences. Kyphoscoliosis and restricted respiratory function are additional important contributory causes of death. Harding observed that approximately 10 percent of these patients have diabetes mellitus and a higher proportion have impaired glucose tolerance; there is both insulin deficiency and peripheral insulin resistance.


Neurology_Adams

Neurology_Adams. Variants of Friedreich ataxia In one important variant of Friedreich ataxia the tendon reflexes are preserved or even hyperactive and the limbs may be spastic. It is the finding of the aberrant frataxin gene that links these unusual cases to Friedreich ataxia; some are associated with hypogonadism. Harding (1981) found 20 such cases among her 200 familial ataxias at the National Hospital, London. Nevertheless, the distinction between classic Friedreich ataxia and ataxia with retained tendon reflexes is an important one clinically, insofar as kyphoscoliosis and heart disease do not occur in the latter group and the prognosis is better. Two of our Friedreich patients had occasional seizures. There are many additional forms of spinocerebellar ataxia, most displaying mainly a cerebellar atrophy, that may simulate Friedreich disease, but due to different mutations. These are taken up below.


Neurology_Adams

Neurology_Adams. Laboratory testing Laboratory tests of diagnostic value are the measurement of sensory nerve conduction velocities and amplitudes, which for the most part are normal because peripheral neuropathy is not a component of the process. Electrocardiography and echocardiography may demonstrate the heart block and ventricular hypertrophy. The CT and MRI seldom reveal a significant degree of cerebellar atrophy but the spinal cord is small. There is no consistent abnormality of blood or CSF and no biochemical abnormalities have been demonstrated. Genetic testing for the length of the GAA trinucleotide repeat segment in FXN is available.


Neurology_Adams

Neurology_Adams. Pathology The spinal cord is thin. The posterior columns and the corticospinal and spinocerebellar tracts are all depleted of myelinated fibers, and there is a mild gliosis that does not replace the bulk of the lost fibers. The nerve cells in the Clarke column and the large neurons of the dorsal root ganglia, especially lumbosacral ones, are reduced in number—but perhaps not to a degree that would fully explain the posterior column degeneration. The posterior roots are thin. Betz cells are also diminished in some cases, but the corticospinal tracts are relatively intact down to the medullary–cervical junction. Beyond this point, they are degenerated, but to a lesser degree than the posterior columns. The nuclei of cranial nerves VIII, X, and XII all exhibit a reduction of cells. Slight to moderate neuronal loss is seen also in the dentate nuclei, and the middle and superior cerebellar peduncles are reduced in size. Some depletion of Purkinje cells in the superior vermis and neurons in


Neurology_Adams

Neurology_Adams. moderate neuronal loss is seen also in the dentate nuclei, and the middle and superior cerebellar peduncles are reduced in size. Some depletion of Purkinje cells in the superior vermis and neurons in corresponding parts of the inferior olivary nuclei can be seen. Many of the myocardial muscle fibers degenerate and are replaced by fibrous connective tissue.


Neurology_Adams

Neurology_Adams. By way of exploring the anatomic basis of the clinical findings, pes cavus is not different from that seen in other neuromuscular diseases of early onset with mild hypertonus of the long extensors and flexors of the feet. There is also cause of amyotrophy of intrinsic foot muscles and foreshortening of the foot when the bones are still malleable. The kyphoscoliosis is probably a result of imbalance of the paravertebral muscles during development. The tabetic aspects of the disease are explained by the degeneration of large cells in the dorsal root ganglia and the large sensory fibers in nerves, dorsal roots, and the columns of Goll and Burdach. The loss of neurons in the sensory ganglia also causes abolition of tendon reflexes. Cerebellar ataxia is attributable to a combined degeneration of the superior vermis and the dentatorubral pathways but also the spinocerebellar tracts, in various combinations. Corticospinal lesions account for the weakness and Babinski signs and contribute to


Neurology_Adams

Neurology_Adams. of the superior vermis and the dentatorubral pathways but also the spinocerebellar tracts, in various combinations. Corticospinal lesions account for the weakness and Babinski signs and contribute to the pes cavus.


Neurology_Adams

Neurology_Adams. Diagnosis Friedreich disease and its variants must be distinguished from familial cerebellar cortical atrophy described next, and from familial spastic paraparesis with ataxia, as well as from peroneal muscular atrophy and the Levy-Roussy syndrome, which are discussed also with the hereditary neuropathies in Chap. 43. It is advisable to assay serum vitamin E levels, as a rare (except in North Africa) but treatable inherited deficiency of a vitamin E transport protein causes a spinocerebellar syndrome with areflexia in children that resembles Friedreich disease (see


Neurology_Adams

Neurology_Adams. Chap. 40). This rare recessive spinocerebellar ataxia associated with vitamin E deficiency arises from mutations in the gene that encodes an alpha tocopherol (vitamin E) transport protein. The absence of dysarthria and of skeletal or cardiac abnormalities in the vitamin-deficiency illness may be helpful. Exceptionally, a cardiac disturbance has been seen in the vitamin deficiency. A form of chronic inflammatory demyelinating polyneuropathy has long since overtaken tabes dorsalis as the most frequent type of areflexic ataxia. It bears a superficial resemblance to Friedreich ataxia when the onset is in early life, but lacks dysarthria and Babinski signs. A form of spinocerebellar degeneration related to human T-cell lymphotrophic virus type I (HTLV-I; Chap. 32), causing so-called tropical spastic paraparesis, as well as the vacuolar myelopathy of HIV multiple sclerosis, syringomyelia, neuroacanthocytosis, and cervical spondylosis, must be included in the differential diagnosis of


Neurology_Adams

Neurology_Adams. spastic paraparesis, as well as the vacuolar myelopathy of HIV multiple sclerosis, syringomyelia, neuroacanthocytosis, and cervical spondylosis, must be included in the differential diagnosis of late-onset cases. Genetic testing settles the matter.


Neurology_Adams

Neurology_Adams. Treatment Not much can be said on this subject because there is little effective therapy. A double-blind crossover study by Trouillas and associates found that the administration of oral 5-hydroxytryptophan modified the cerebellar symptoms. This has not been tested in another study. Apart from this form of treatment, with which we have had no experience, no therapeutic measures are known to alter the course of the disease. In several small trials, idebenone, an antioxidant (the short-chain analogue of coenzyme Q10), reduced the progression of left ventricular hypertrophy, a risk factor for arrhythmias and sudden death in these patients, but this could not be confirmed in subsequent trials. These results are summarized in an article by Filla and Moss. Heart failure, arrhythmias, and diabetes mellitus are treated by the usual medical measures and it bears repetition that careful evaluation of the cardiac disorder may prevent premature death. Surgery for scoliosis and foot deformities


Neurology_Adams

Neurology_Adams. mellitus are treated by the usual medical measures and it bears repetition that careful evaluation of the cardiac disorder may prevent premature death. Surgery for scoliosis and foot deformities may be helpful in selected cases.


Neurology_Adams

Neurology_Adams. Given the mechanism involved in putative epigenetic silencing of the gene, histone deacetylase inhibitors are being investigated as potential disease modifying agents. One such agent is nicotinamide, a form of vitamin B3. Early stage trials have shown an increase in frataxin expression following treatment with nicotinamide in Friedreich ataxia patients. Gene therapy as a potential disease modifying agent is also under investigation, with introduction of a fully functional frataxin minigene into cells using an adeno-associated virus.


Neurology_Adams

Neurology_Adams. Soon after the publication of Friedreich’s descriptions of a spinal type of hereditary ataxia, reports began to appear of somewhat different diseases in which the ataxia was related to degenerative changes in the cerebellum and brainstem rather than in the spinal cord. Claims of their independence from the spinal type were based largely on a later age of onset, a more definite hereditary transmission (usually of autosomal dominant type), the persistence or hyperactivity of tendon reflexes, and associations with ophthalmoplegia, retinal degeneration, and optic atrophy. Several of these clinical features, particularly briskness of tendon reflexes, are alien to the classic form of Friedreich ataxia.


Neurology_Adams

Neurology_Adams. By 1893, Pierre Marie thought it desirable to create a new category of hereditary ataxia that would embrace all of the non-Friedreich cases. He collated the familial cases of progressive ataxia that had been described by Fraser, Nonne, Sanger Brown, and Klippel and Durante (see both Greenfield and Harding [1993] for references) and proposed that all of them were examples of an entity to which he applied the name hérédo-ataxie cérébelleuse. Marie’s proposition (see Marie et al) was based almost entirely on clinical observations not his own but those made by the aforementioned authors. Later, as members of these families died, postmortem examinations disclosed that Marie’s hereditary cerebellar ataxia included not one but several disease entities. Indeed, as pointed out by Holmes (1907b) and later by Greenfield, in 3 of 4 families the cerebellum showed no significant lesions at all. Yet there was by then no doubt of the existence of a separate class of predominantly cerebellar


Neurology_Adams

Neurology_Adams. and later by Greenfield, in 3 of 4 families the cerebellum showed no significant lesions at all. Yet there was by then no doubt of the existence of a separate class of predominantly cerebellar atrophies, some purely cortical and others associated with a variety of noncerebellar disorders.


Neurology_Adams

Neurology_Adams. Holmes (1907a) described a family of 8 siblings, of whom 3 brothers and 1 sister were affected by a progressive ataxia, beginning with a reeling gait and followed by clumsiness of the hands, dysarthria, tremor of the head, and a variable nystagmus, but without additional features to implicate disease of the spinal cord or brainstem. It may be taken as the prototype of pure cerebellar cortical degeneration. The main distinction from multiple system atrophy with cerebellar degeneration is that the Holmes type spares the pontine nuclei.


Neurology_Adams

Neurology_Adams. The ataxia begins insidiously, usually in the fourth decade but with very wide variability in age of onset, and progresses slowly over many years. Ataxia of gait, instability of the trunk, tremor of the hands and head, and slightly slowed, hesitant speech is the usual clinical picture. Nystagmus is rare and intelligence is usually preserved. The patellar reflexes may be slightly increased but this may be apparent based on the pendular character of reflexes in cerebellar disease; the plantar reflexes are flexor and the ankle jerks are present but there are exceptions and probably mark the process as one of the other genetic ataxias. This clinical syndrome probably can result from several genetically determined processes, some of which declare themselves as the illness progresses by displaying characteristic signs other than ataxia. The differential diagnosis in the nonfamilial cases is even broader, including many acquired types of ataxias discussed in Chap. 5 (see Table 5-3).


Neurology_Adams

Neurology_Adams. Pathology Postmortem examination of the Holmes type cases discloses symmetrical atrophy of the cerebellum involving mainly the anterior lobe and vermis, the latter being more affected. Purkinje cells are absent in the lingula, centralis, and pyramis of the superior vermis and reduced in number in the quadrangularis, flocculus, biventral, and pyramidal lobes. The other cerebellar cortical neurons and granule cells and dorsal and medial parts of the inferior olivary nuclei are diminished less so. The white matter is slightly pale in myelin stains. The vermian atrophy and that of adjacent parts of the cerebellum can be visualized with clarity in MRIs (Fig. 38-8).


Neurology_Adams

Neurology_Adams. The vague similarity of the pathologic (and clinical) changes to those of alcoholic cerebellar degeneration is at once apparent and should raise the question of an alcoholic-nutritional cause in sporadic cases (see Chap. 40); in serious alcohol-nutritional disease, there usually is an accompanying polyneuropathy and reduced ankle reflexes.


Neurology_Adams

Neurology_Adams. This type of developmental delay, caused by an unstable extended trinucleotide repeat sequence and breakage of the X-chromosome, is discussed in Chap. 36. Here we refer to an unusual variant of the degenerative process with onset in midor late adulthood, mainly but not exclusively in men, and consisting of gait or limb ataxia and mild tremor. The process affects carriers of a “premutation” who have 50 to 200 CGG repeat sequences in the FMR1 gene, who may manifest tremor and ataxia late in life. The full mutation is better known as a cause of a developmental delay and autistic-like syndrome in boys (Chap. 37). The frequency of the premutation is approximately 1 in 150 to 300 females, and 1 in 400 to 850 males. In contradistinction to the full mutation of over 200 repeats, there is apparently a buildup of messenger ribonucleic acid (mRNA) in the adult form that interferes in some way with cellular function. As a result of anticipation across generations, it was found that fragile X


Neurology_Adams

Neurology_Adams. a buildup of messenger ribonucleic acid (mRNA) in the adult form that interferes in some way with cellular function. As a result of anticipation across generations, it was found that fragile X often emerges in a boy whose maternal grandfather had the premutation-tremor syndrome. Aggregating several studies, the frequency of this genetic abnormality among otherwise unassignable adult ataxia cases is less than 10 percent.


Neurology_Adams

Neurology_Adams. The entire clinical spectrum has yet to be defined but our experience has featured mild progressive gait ataxia in the sixth decade that was misattributed to normal- pressure hydrocephalus and an intermittent hand tremor that was probably ataxic in nature. Some reports have included a parkinsonian syndrome and more consistently, a mild frontal dementia, making the distinction from frontotemporal dementia difficult. Many cases have been confused with multiple system atrophy. T2 hyperintensity in the cerebellar peduncles are characteristic of some cases, but this was not found in our patients, which showed only midline cerebellar atrophy. A family history of developmental delay or autistic spectrum disorder may be a hint to diagnosis and some proportion of individuals with the premutation also have a nonprogressive cognitive deficiency.


Neurology_Adams

Neurology_Adams. A study of the neuropathology by Greco and colleagues showed cerebral and cerebellar spongiform white matter changes and both intranuclear and astrocytic inclusions. Their report demonstrated a correspondence between the quantity of trinucleotide repeats and the number of inclusion bodies.


Neurology_Adams

Neurology_Adams. A sporadically occurring disorder closely resembling the Holmes type of cortical cerebellar degeneration but with additional features of brainstem atrophy was described in 1900 by Dejerine and André-Thomas, who named it olivopontocerebellar atrophy (OPCA). As more cases of this type were collected, an autosomal dominant hereditary pattern was evident in some, and one or more long tracts in the spinal cord were found to have degenerated. About half the cases later developed the parkinsonism with degeneration of nigral cells and, in a few, of striatal cells, thereby marking the disease as a form of striatonigral degeneration that is essentially a type of multiple system atrophy (MSA-C) as discussed in detail in an earlier section and also below. The main distinction from the Holmes type is that MSA-C involves degeneration of the ponto-cerebellar and olivocerebellar fibers.


Neurology_Adams

Neurology_Adams. Notable findings in both the sporadic and the familial forms of many of the variants of cerebellar atrophy are extensive degeneration of the middle cerebellar peduncles, cerebellar white matter, and pontine, olivary, and arcuate nuclei; loss of Purkinje cells has been variable. Most likely this degeneration represents a “dying back” of axons of the cerebellar, pontine, and olivary nuclei with secondary myelin degeneration. Extreme atrophy of the medullary olivary nuclei may be evident on MRIs but is usually more subtle (Fig. 38-9). In a personally observed series of 12 definite cases and a larger number of probable cases of MSA-C, our colleague Schmahmann (Lin et al) described autonomic features and REM-sleep behavior disorder and an older age of onset, and a faster disease progression as distinguished from idiopathic-sporadic late onset forms of cerebellar ataxias; both categories can have associated extrapyramidal features. Their series had a mean age of onset of symptoms of


Neurology_Adams

Neurology_Adams. as distinguished from idiopathic-sporadic late onset forms of cerebellar ataxias; both categories can have associated extrapyramidal features. Their series had a mean age of onset of symptoms of approximately the middle of the sixth decade and urinary dysfunction and erectile were particularly common.


Neurology_Adams

Neurology_Adams. Other complex forms of cerebellar degeneration Certain clinical constellations are recognizable and clinically useful. They were denominated by the person who described them or by a particular clinical feature but they are now classified as spinocerebellar ataxias (degenerations) and their genetic source (Table 38-5). For example, Konigsmark and Weiner subdivided these disorders into several types, including a dominantly inherited OPCA (of Menzel); a recessive type (of Fickler-Winkler); a dominant type with retinal degeneration; one with spastic paraplegia and areflexia; and with dementia, ophthalmoplegia, and extrapyramidal signs. To these had been added cases of OPCA with neuropathy and slowed eye movements (Wadia type), of which we have seen 2 cases, and cases with dystonia and a variety of other clinical findings, most in single families (hemiballismus, athetosis, contractures of the legs, fixed pupils, ophthalmoplegia, ptosis, gaze palsy, deafness, retinal degeneration, mental


Neurology_Adams

Neurology_Adams. of other clinical findings, most in single families (hemiballismus, athetosis, contractures of the legs, fixed pupils, ophthalmoplegia, ptosis, gaze palsy, deafness, retinal degeneration, mental retardation and epilepsy, claw foot and scoliosis, incontinence, parkinsonian symptoms and signs, plethora of presentations including a neonatal type). Some of these are detailed below.


Neurology_Adams

Neurology_Adams. Cases of sporadic olivopontocerebellar atrophy are more common than the familial variety and tend to occur at an older age; nystagmus, optic atrophy, retinal degeneration, ophthalmoplegia, and urinary incontinence are generally not observed. However, there are numerous cases that include mild extrapyramidal and neuropathic signs, slow eye movements, dystonia, impairment of vertical saccadic eye movements (thus simulating progressive supranuclear palsy), vocal cord paralysis, all of which mark the process as multiple system atrophy (MSA-C) or Machado-Joseph-Azorean disease (SCA3, discussed below), and some cases with deafness.


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Neurology_Adams. This entity of MSA-C has been discussed with the degenerative disorders of the basal ganglia earlier in the chapter. Here it is pointed out that a number of cases of sporadic progressive ataxia in mid and late life are attributable to this process and have been termed MSA-C to signify the predominant cerebellar feature. The extrapyramidal, corticospinal, or autonomic aspects of the illness may or may not become evident with continued observation or by pathologic examination. Some guidance as to the frequency of MSA as the cause of otherwise undifferentiated sporadic ataxia is given in the study by Abele and colleagues who found that it accounts for almost one-third of cases, but the precise number is open to question as pathologic examinations were not made. Machado-Joseph-Azorean Disease (SCA3, ATXN3)


Neurology_Adams

Neurology_Adams. A special form of hereditary ataxia with brainstem and extrapyramidal signs has been described in patients mainly, but not exclusively, of Portuguese-Azorean origin. The disorder is characterized by an autosomal dominant pattern of inheritance and by a slowly progressive ataxia beginning in adolescence or early adult life in association with one or more features of dysarthria, hyperreflexia, extrapyramidal rigidity, dystonia, and as the illness evolves, bulbar signs, distal motor weakness, polyneuropathy, or ophthalmoplegia. There is usually no impairment of intellect and in the examples the authors have seen, the extrapyramidal symptoms were mainly rigidity and slowness of movement. Early Machado-Joseph disease characteristically demonstrates the finding of dysmetric horizontal and vertical saccades, even before the ataxia is obvious (Hotson et al). This conjunction of a parkinsonian syndrome with cerebellar ataxia is suggestive of MSA-C except for an earlier age of onset and the


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Neurology_Adams. saccades, even before the ataxia is obvious (Hotson et al). This conjunction of a parkinsonian syndrome with cerebellar ataxia is suggestive of MSA-C except for an earlier age of onset and the prominence in some cases of dystonia, amyotrophy, and ophthalmoplegia in Machado-Joseph. Postmortem examination discloses a degeneration of the dentate nuclei and spinocerebellar tracts and a loss of anterior horn cells and neurons of the pons, substantia nigra, and oculomotor nuclei. Cancel and colleagues found an unstable number of CAG repeating sequences in ataxin-3, and named the disorder spinocerebellar ataxia type 3 (SCA3).


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Neurology_Adams. An affected Azorean family named Joseph was described in 1976 by Rosenberg and colleagues under the name of autosomal dominant striatonigral degeneration. Using the term Azorean disease of the nervous system (now better known as Machado-Joseph disease), Romanul and colleagues described yet another family of Portuguese-Azorean descent, many members of which were affected by a syndrome comprising a progressive ataxia of gait, parkinsonian features, limitation of conjugate gaze, fasciculations, areflexia, nystagmus, ataxic tremor, and extensor plantar responses; the pathologic changes closely resembled those described by Woods and Schaumburg. Romanul and coworkers compared the genetic, clinical, and pathologic features of their cases with those described in other Portuguese-Azorean families and concluded that all of them represent a single genetic entity with variable expression. This concept of the disease has been corroborated by the further observations of Rosenberg and of Fowler who


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Neurology_Adams. and concluded that all of them represent a single genetic entity with variable expression. This concept of the disease has been corroborated by the further observations of Rosenberg and of Fowler who studied 20 patients with the Machado-Joseph-Azorean disease over a 10-year period and more recently by genetic testing.


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Neurology_Adams. The disease is not limited to Azoreans. Cases conforming to the above descriptions have now been observed among African American, Indian, and Japanese families (Sakai et al; Yuasa et al; Bharucha et al). There are no signs of polyneuropathy, which is the main feature of another disease in Portuguese emigrants caused by amyloid deposition, described by Nakano and colleagues as “Machado disease,” this being the name of the progenitor of the afflicted family. In fully developed cases, the MRI findings are of reduced width of the superior and middle cerebellar peduncles, atrophy of the frontal and temporal lobes, and smallness of the pons and globus pallidus (Murata et al). There is no treatment of proven value. Dentatorubropallidoluysian Atrophy (DRPLA, ATN1)


Neurology_Adams

Neurology_Adams. This is a rare familial disorder, described mostly in Japan and in small European pockets, in which symptoms of cerebellar ataxia are coupled with those of choreoathetosis and dystonia and, in some instances, parkinsonism, myoclonus, epilepsy, or dementia. Pathologically there is degeneration of the dentatorubral and pallidoluysian systems. The main consideration when chorea is a prominent feature is the separation of this disorder from Huntington disease. The gene defect in DRPLA is an unstable CAG trinucleotide repeat in ATN1, which codes for the protein atrophin 1. This same mutation has been defined in affected families from throughout the world (e.g., Warner et al). Clinical manifestations are usually associated with 48 to 93 repeat triplets as compared to 7 to 35 in the general population. As with Huntington chorea (where the expanded polyglutamine sequence is in the protein huntingtin), this disease is inherited as an autosomal dominant trait and shows an inverse correlation


Neurology_Adams

Neurology_Adams. As with Huntington chorea (where the expanded polyglutamine sequence is in the protein huntingtin), this disease is inherited as an autosomal dominant trait and shows an inverse correlation between the age of onset and the size of the gene expansion (anticipation). When chorea predominates early in the illness, there may be difficulty distinguishing DRPLA from Huntington disease. The pathology has been summarized by Iizuka and colleagues. The diagnosis is confirmed by sequencing of the affected gene.


Neurology_Adams

Neurology_Adams. Dentatorubral degeneration This is a rare and still nebulous entity but it may be distinct from DRPLA. There are several instructive features and is listed here partly for historical reasons. In 1921, Ramsay Hunt published an account of 6 patients (2 of whom were twin brothers) in whom myoclonus was combined with progressive cerebellar ataxia. The age of onset in the 4 nonfamilial cases was between 7 and 17 years, and the cerebellar ataxia followed the myoclonus by an interval of 1 to 20 years. Hunt named the disorder dyssynergia cerebellaris myoclonica. There were signs of Friedreich ataxia in the twin brothers; postmortem examination of one showed cerebellar atrophy, degeneration of the posterior columns and spinocerebellar tracts but not of the corticospinal tracts. In 1947, Louis-Bar and van Bogaert reported a similar case and noted, in addition to the above findings, degeneration of the corticospinal tracts and loss of fibers in the posterior roots. Thus, the pathology was


Neurology_Adams

Neurology_Adams. and van Bogaert reported a similar case and noted, in addition to the above findings, degeneration of the corticospinal tracts and loss of fibers in the posterior roots. Thus, the pathology was identical to that of Friedreich ataxia in their case except for the more severe atrophy of the dentate nuclei.


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Neurology_Adams. Earlier (1914), under the title dyssynergia cerebellaris progressiva, Hunt had drawn attention to a progressive disease in young individuals manifest by what he considered to be a pure cerebellar syndrome but one of his cases was revealed at autopsy to be Wilson disease. Hunt’s reports emphasize the hazard of classifying cerebellar ataxias on the basis of clinical findings alone, a point made effectively by Holmes. Paroxysmal Ataxias (See Also Chap. 5) Two adult forms of hereditary cerebellar ataxia are paroxysmal in nature. In one (EA-2 for “episodic ataxia, type 2”), the episodes occur without explanation and last several hours; vertigo is the prominent feature of the attacks. Between attacks the patient is normal or has only minimal ataxia and nystagmus (Griggs et al). These ataxic episodes are prevented strikingly by the administration of oral acetazolamide. The disorder has been found to be a mutation of the calcium channel gene on chromosome 19 as listed in Table 38-5.


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Neurology_Adams. A similar but physiologically and genetically unrelated paroxysmal ataxia (EA-1) is characterized by episodes that may be precipitated by exercise and by the presence of muscle myokymia (rippling) between attacks. Vertigo does not occur and acetazolamide is less effective or not effective at all. The disorder is caused by an abnormality of the potassium channel gene on chromosome 12 (see Table 38-5). Both of these episodic ataxias are therefore “channelopathies” (differing from the muscular and neuromuscular disorders discussed in Chap. 46). Also of interest is spinocerebellar atrophy type 6, a progressive condition in which a mutation has been traced to same gene implicated in the EA-2 acetazolamide-responsive paroxysmal ataxia, but this disorder is not paroxysmal and results in progressive ataxia, dysarthria, and loss of proprioception. Differential Diagnosis of the Degenerative Ataxias in Adults (See Also Table 5-3)


Neurology_Adams

Neurology_Adams. Differential Diagnosis of the Degenerative Ataxias in Adults (See Also Table 5-3) Sporadic forms of cerebellar ataxia in adults are in some instances traceable to strokes involving cerebellar pathways (Safe et al). These are, of course, of acute onset. Some cases of ataxia are alcoholic-nutritional in origin, and a few are related to excessive use of drugs or therapeutic medications, especially antiepileptic drugs, which may in a few cases cause a slowly progressive and permanent ataxia. The paraneoplastic variety of cerebellar degeneration often enters into the differential diagnosis; it occurs mostly in women with breast or ovarian cancers and evolves much more rapidly than any of the heredodegenerative forms. The more rapid onset of ataxia and the presence of anti-Purkinje cell antibodies (anti-Yo; see “Paraneoplastic Cerebellar Degeneration” in


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Neurology_Adams. Chap. 30) are central to identifying the nature of this disease. In adult practice, many instances that are not attributable to a paraneoplastic disorder or to alcohol-nutritional deficiency turn out to be, or at least are attributed to, multiple system atrophy, cerebellar type. Organic mercury induces subacute cerebellar degeneration, and adulterated heroin causes a more abrupt and severe ataxic syndrome. Rare cases of ataxia have been associated with celiac disease and Whipple disease, and metronidazole as noted in Chap. 5. Ataxia may also be an early and prominent manifestation of Creutzfeldt-Jakob disease caused by a prion (see Chap. 32) or of an inherited metabolic disease (see Chap. 36). Of the latter, late-onset GM2 gangliosidosis may simulate cerebellar degeneration in adults. Rare cases of aminoacidopathy manifesting for the first time in adult life have also provoked a cerebellar syndrome (see Chap. 36).


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Neurology_Adams. The syndrome of quick, arrhythmic, involuntary single or repetitive twitches of a muscle or group of muscles was described in Chap. 4, where it was pointed out that the condition has many causes. Chapter 36 discusses those caused by hereditary metabolic diseases. Familial forms are known, one of which, associated with cerebellar ataxia, was discussed earlier (dyssynergia cerebellaris myoclonica of Ramsay Hunt). But there is another disease, known as hereditary essential benign myoclonus, that occurs in relatively pure form unaccompanied by ataxia (termed essential, or familial, myoclonus; see Chap. 4). In this condition, it is difficult to evaluate coordination because willed movement is interrupted by myoclonus that may be mistaken for intention tremor. Only by slowing the voluntary movement can the myoclonus be reduced or eliminated. This myoclonic disease is inherited as an autosomal dominant trait. It becomes manifest early in life; once established, it persists with little or no


Neurology_Adams

Neurology_Adams. can the myoclonus be reduced or eliminated. This myoclonic disease is inherited as an autosomal dominant trait. It becomes manifest early in life; once established, it persists with little or no change in severity throughout life, often with rather little disability. It can, by its natural course, be differentiated from some of the hereditary metabolic diseases such as the Unverricht and Lafora types of myoclonic epilepsy, the lipidoses, tuberous sclerosis, and myoclonic disorders that follow certain viral infections and anoxic encephalopathy. Of interest is the response of this form of movement disorder to certain pharmacologic agents, notably clonazepam, valproic acid, and 5-hydroxytryptophan, the amino acid precursor of serotonin, particularly when these agents are used in combination (postanoxic myoclonus responds to the same medications).


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Neurology_Adams. Another form of nonprogressive myoclonus, dominantly inherited, is associated with dystonia, which is due to a mutation in a sarcoglycan gene, SGCE. The main clinical distinctions are from juvenile myoclonic epilepsy (see Chap. 15), drug-induced myoclonus, particularly lithium and opiates; renal failure and other acquired metabolic disorders; asterixis; and from the startle responses and some of the diseases that have this sign as their main characteristic (see Chap. 4). Creutzfeldt-Jakob subacute spongiform encephalopathy may cause difficulty in diagnosis initially but the course of illness clarifies the situation rapidly. Myoclonus is also one component of the complex movement disorder in corticobasal-ganglionic degeneration that was described in an earlier section. The place in nosology of the hyperekplexias, and in particular their relation to the myoclonias, is uncertain.


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Neurology_Adams. The place in nosology of the hyperekplexias, and in particular their relation to the myoclonias, is uncertain. This general term designates a group of progressive degenerative disorders of motor neurons in the spinal cord, brainstem, and motor cortex, manifest clinically by muscular weakness, atrophy, and corticospinal tract signs in varying combinations. It is for the most part a disease of middle life and progresses to death in a matter of 2 to 5 years or longer in exceptional cases.


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Neurology_Adams. Customarily, motor system disease is subdivided into several subtypes on the basis of the grouping of symptoms and signs. The most frequent form, in which amyotrophy and hyperreflexia are combined, is ALS (amyotrophy is the term applied to denervation atrophy and weakness of muscles). Less frequent are cases in which weakness and atrophy occur alone, without evidence of corticospinal tract dysfunction; for these the term progressive muscular atrophy is used. When the weakness and wasting predominate in muscles innervated by the motor nuclei of the lower brainstem (i.e., muscles of the jaw, face, tongue, pharynx, and larynx), it is customary to speak of progressive bulbar palsy. In a small proportion of patients, the clinical state is dominated by spastic weakness, hyperreflexia, and Babinski signs, with lower motor neuron aspects becoming apparent only at a later stage of the illness, or not at all. This is designated primary lateral sclerosis, an infrequent form of motor system


Neurology_Adams

Neurology_Adams. Babinski signs, with lower motor neuron aspects becoming apparent only at a later stage of the illness, or not at all. This is designated primary lateral sclerosis, an infrequent form of motor system disease in which the degenerative process remains confined to the corticospinal pathways, sparing the anterior horn cells (Pringle et al); it’s relation to ALS has always been a matter of uncertainty. The pure spastic paraplegias without amyotrophy may represent a special class of disease hence they are described separately. There are also relatively common familial forms of spastic paraplegia in which the disease is confined to the corticospinal tracts or, in some cases, combined with posterior column or other neurologic signs.


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Neurology_Adams. Furthermore, an important group of special spinal muscular atrophies occurs in infancy and childhood and are the leading cause of heritable infant mortality and, after cystic fibrosis, the most frequent form of serious childhood autosomal recessive disease (Pearn). The best known is the Werdnig-Hoffmann type of infantile spinal muscular atrophy (SMA type I); but there are other forms beginning in later childhood, adolescence, or early adult life (SMA types II and III, or the Wohlfart-Kugelberg-Welander type). Despite the clinical heterogeneity of the heritable childhood spinal muscular atrophies, they all derive from mutations in the SMN gene (see below; see Gilliam et al; Brzustowicz et al). This group of early-onset spinal muscular atrophies is separate genetically from a familial form of ALS.


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Neurology_Adams. History Credit for the original delineation of amyotrophic lateral sclerosis is appropriately given to Charcot. With Joffroy in 1869 and Gombault in 1871, he studied the pathologic aspects of the disease. In a series of lectures given from 1872 to 1874, he provided a lucid account of the clinical and pathologic findings. Although called Charcot disease in France, amyotrophic lateral sclerosis (the term recommended by Charcot) has been preferred in the English-speaking world. Duchenne had earlier (1858) described labioglossolaryngeal paralysis, a term that Wachsmuth in 1864 changed to progressive bulbar palsy. In 1869, Charcot called attention to the nuclear origin of progressive bulbar palsy, and in 1882 Dejerine established its relationship to ALS. Most authors credit Aran and Duchenne with the earliest descriptions of progressive spinal muscular atrophy, which they believed to be of myogenic origin. This interpretation was, of course, incorrect; Cruveilhier, a few years later, noted


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Neurology_Adams. the earliest descriptions of progressive spinal muscular atrophy, which they believed to be of myogenic origin. This interpretation was, of course, incorrect; Cruveilhier, a few years later, noted the slender anterior roots, and soon thereafter the disease was brought into line with ALS as a spinal muscular atrophy. The genetic discovery in relation to this disease that opened a new chapter in understanding the disease was the discovery of the mutation in the superoxide dismutase (SOD1) gene in familial cases of motor neuron disease. Several other sporadic mutations followed in succession and together are considered to explain a number of what were classified as sporadic cases.


Neurology_Adams

Neurology_Adams. Epidemiology This is a disease commonly encountered by neurologists, with an annual incidence rate of 0.4 to 1.76 per 100,000 population. Men are affected nearly twice as often as women. Most patients are older than age 45 years at the onset of symptoms, and the incidence increases with each decade of life (Mulder et al). The disease occurs in a random pattern throughout the world except for a dramatic clustering of patients among inhabitants of the Kii peninsula in Japan and in Guam, where ALS is often combined with dementia and parkinsonism.


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Neurology_Adams. In approximately 10 percent of cases the disease is familial, being inherited as an autosomal dominant trait with age-dependent penetrance. The familial cases differ in their symptoms and clinical course from nonfamilial ones; as a group they have an earlier age of onset, an equal distribution in men and women, and a slightly shorter survival. Environmental associations are reported from time to time, for example, among soldiers who had served in various regions and were exposed to toxins such as agent orange. A traumatic origin of some cases has been raised on the basis of circumstantial evidence of an increased incidence in Americal and Italian Football players (Chio et al, 2005), often coincident with the tauopathy, chronic traumatic encephalopathy. These epidemiologic associations are uncertain but further exploration is warranted.


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Neurology_Adams. Clinical features In the most typical forms of disease, the onset is perceived by the patient as weakness in a distal part of one limb. This is noted first as an unexplained tripping from slight foot-drop, or by awkwardness in tasks requiring fine finger movements (handling buttons and automobile ignition keys), stiffness of the fingers, and slight weakness or wasting of the hand muscles on one side. In other words, features related to upper and to lower motor neuron degeneration (or both) may appear insidiously in one limb. Cramping beyond what seems natural and fasciculations of the muscles of the forearm, upper arm, and shoulder girdle may also arise. The earliest manifestation of the lower motor neuron component of this disease is sometimes volitional cramping—for example, leg cramps as the patient turns in bed during the early morning hours.


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Neurology_Adams. As the weeks and months pass, the other hand and arm become similarly affected with weakness, stiffness, slowness, atrophy or cramps. Before long, the triad of atrophic weakness of the hands and forearms, fasciculations, slight spasticity of the arms or legs, and generalized hyperreflexia—all in the absence of sensory change—leaves little doubt as to the diagnosis. Muscle strength and bulk diminish in parallel or there is a relative preservation of power early in the illness. Despite the amyotrophy, the tendon reflexes are notable for their liveliness. Babinski and Hoffmann signs are variably present; surprisingly, they may not appear even as the illness progresses. Abductors, adductors, and extensors of fingers and thumb tend to become weak before the long flexors, on which the handgrip depends, and the dorsal interosseous spaces become hollowed, giving rise to the “cadaveric” or “skeletal” hand. The muscles of the upper arm and shoulder girdles are typically involved later. There is


Neurology_Adams

Neurology_Adams. and the dorsal interosseous spaces become hollowed, giving rise to the “cadaveric” or “skeletal” hand. The muscles of the upper arm and shoulder girdles are typically involved later. There is a general tendency for adjacent areas to be involved before more distant ones. When an arm is the first limb affected, all this occurs while the thigh and leg muscles seem relatively normal, and there may come a time in some cases when the patient walks about with useless, dangling arms. Later the atrophic weakness spreads to the neck, tongue, pharyngeal, and laryngeal muscles, and eventually those in the trunk and lower extremities yield to the onslaught of the disease.


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Neurology_Adams. The affected parts may ache and feel cold, but true paresthesias, except from poor positioning and pressure on nerves, do not occur or are minor. Sphincteric control is well maintained even after both legs have become weak and spastic, but many patients acquire urinary and sometimes fecal urgency in the advanced stages of the disease. The abdominal reflexes may be elicitable even when the plantar reflexes are extensor. Extreme spasticity is rarely seen. Coarse fasciculations are usually evident in the weakened muscles but may not be noticed by the patient until the physician calls attention to them. Fasciculations are almost never the sole presenting feature of ALS—a clinical truism with which one can reassure physicians and medical students who fear, on the basis of persistent focal muscle twitching in the thumb, face, foot, periocular or periorbital muscles, that they are developing the disease.


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Neurology_Adams. The course of this illness, irrespective of its particular mode of onset and pattern of evolution, is progressive. There may be periods lasting weeks or months during which the patient observes no advance in symptoms but clinical changes can nonetheless be detected. Half the patients succumb within 3 years of onset and 90 percent within 6 years (Mulder et al). Several clinical variations that occur with regularity and have distinguishing clinical features are described below.


Neurology_Adams

Neurology_Adams. Other patterns of clinical evolution In addition to the special configurations discussed further on, there are many patterns of neuromuscular involvement other than the one just described. A leg may be affected before the hands. A foot-drop with weakness and wasting of the pretibial muscles may be incorrectly attributed to peroneal nerve compression until weakness of the gastrocnemius and other muscles betray more widespread involvement of lumbosacral neurons. In our experience, this crural amyotrophy has been less frequent than the brachial-manual type. Another variant is early involvement of thoracic, abdominal, or posterior neck muscles, the last being one of the causes of head lolling and camptocormia (forward bending of the neck and trunk) in older individuals. Yet another pattern 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