Dystonias
If not idiopathic, dystonias can be caused by a variety of neurological disorders. Their classification can be based on age of onset, by body distribution or by etiology. Secondary dystonias are often accompanied by other neurological deficits, occur at rest and are associated with different hereditary and environmental causes. Certain patterns of dystonia can be recognized in certain disease entities. Focal brain lesions are commonly associated with hemidystonia whereas focal forms tend to appear in certain neurodegenerative disorders e.g. oculofaciocervical dystonia (progressive supranuclear palsy).
Drug/toxin-induced dystonia: Tardive dystonia or dyskinesia may follow the use of antipsychotic drugs (prevalence 15-20%) or other dopamine receptor blocking agents as well as levodopa or dopamine agonist therapy, buspirone, SSRIs, AEDs (phenytoin, carbamazepine and gabapentin). Tardive dyskinesia present typically with oro-buccal-lingual dyskiensias. Spontaneous remission is low (14%) and occurs on average 2.5 years after discontinuation of the neuroleptic drug. Refractory forms may be treated with pallidal deep brain stimulation. Manganese poisoning causes parkinsonism with prominent dystonia. Delayed leucoencephalopathy and pallidal necrosis may follow anoxic brain damage caused by carbon monoxide poisoning. In that case MRI may reveal bilateral basal ganglia hypodensities and watershed infarctions.
Primary torsion dystonia (PTD) or Ziehen-Oppenheim disease: PTD is highly variable, ranging from severe disabling generalized dystonia in childhood to mild focal dystonia appearing in later life. Adult onset forms are rare (1-2%), and may be sporadic or familial (autosomal dominant) with low penetrance (30%) and variable expression. PTD commonly appears in 4th to 6th decade and is usually segmental or focal in nature. There is a distinct age-related anatomical distribution in dystonia: while early onset PTD affects the legs, later onset focal PTD usually affects upper limbs, cranial or axial muscles (writer cramp, torticollis, blepharospasm, oromandibular dystonia, laryngeal dystonia, hemifacial spasm and axial dystonia). Excitement worsens the conditions and sleep abolishes it. To date, at least 12 types of primary dystonia can be distinguished on genetic basis. In families containing patients with early-onset PTD, there may be members with mild late-onset focal dystonia or simply tremor or stuttering, or asymptomatic carries. Essential in the differential diagnosis of PTD is that the neurological examination is normal, there are no seizures or dementia. The DYT1 gene encoding for torsin A is located on chromosome 9q34 and is transmitted autosomal dominant. Oral treatment is often unrewarding, but globus pallidus deep brain stimulation looks promising.
Hemifacial spasm may be idiopathic, are caused by neurovascular/tumoral compression of the facial nerve or brainstem lesions (e.g. MS). Finally it can be a sequel of Bell palsy. Early cases may be difficult to distinguish from myokymia. EMG of the facial nerve with blink reflex are diagnostic. MRI should be performed particularly in young patients. When neurovascular compression is suspected an angiography is required. The most helpful agents in the early stages are botox injections, carbamazepine, baclofen and clonazepam.
Dopa-responsive dystonia (DRD)
or Segawa syndrome:
DRD is an autosomal dominant (DYT5a) or recessive disease (DYT5b), which typically presents in
childhood and early adolescence. However disease onset has been described up to
the 2nd and early 3rd decades. The female to male ratio is
3:2. Features suggestive of lower extremity spasticity (brisk deep-tendon
reflexes, ankle clonus, frequent falls and/or dystonic extension of the big toe
[the striatal toe]) with diurnal variation (symptoms disappear after sleep and worsen as the
day progresses) may be present and are often misdiagnosed as spastic diplegia.
Cognitive function is normal. The late-onset forms are considered a form fruste
of DRD and may present as prominent but nonprogressive
levodopa responsive parkinsonism or
oromandibular dystonia in the elderly. In contrast to lower limb dystonia
observed in early-onset IPD there is a dramatic sustained response to low doses
of oral levodopa (275 mg tid for 3 months) and not associated with
levodopa-induced dyskinesias. DRD is caused by deficit of
5,6,7,8-tetrahydrobiopterin (BH4). Biochemically, the disorder is typically
characterized by low levels of the CNS dopamine metabolite, HVA, and reduced
levels of neopterin and BH4 in the CSF.
This is due to heterozygote mutations of the GTP cyclohydrolase I (GTPCH1) gene, which is
the rate-limiting enzyme in the synthesis of BH4. The latter is an essential
cofactor for tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of
dopamine. Reduced levels of BH4 lead to the dopamine-deficiency syndrome DRD
because of reduced TH activity. Measurement of the concentration of total
biopterin (most of which exists as BH4) and neopterin (the by-products of the
GTPCH1 reaction) in CSF is useful for the diagnosis of GTPCH1-deficient DRD.
Brain MRI is normal. The disease progresses markedly in the first 15 years, with
postural dystonia progressing to all 4 limbs (even in the morning) by the end of
the 2nd decade. Progression slows in the 3rd decade and
plateaus thereafter. Mutations in the GCH1 gene (chromosomal locus 14q22.1-q22.2) coding for the enzyme GTPCH1
can cause autosomal dominant DRD, and mutations in the TH gene
(chromosomal locus 11p15.5) coding for the enzyme TH can cause
autosomal recessive DRD (the mild form of TH deficiency). The
phenylalanine loading test with a single sample being taken for phenylalanine
and tyrosine 4 hours after loading can be used to differentiate DRD from PTD.
The phenylalanine/tyrosine ratio in patients with DRD is pathologic (above 7.5).
Rapid-onset
dystonia-parkinsonism (RDP):
The disorder is autosomal dominant, generally occuring during adolescence or
early adulthood, and is characterized by sudden fast onset (over hours or days) of severe persistent primarily bulbar and upper
limb dystonia, parkinsonism (bradykinesia, and postural instability),
dysarthria, dysphagia. The symptoms
generally stabilize within a few weeks, with no improvement. Levels of HVA may
be decreased in severely affected patients and in asymptomatic gene carriers.
Treatment with levodopa provides little benefit. The locus for RDP (DYT12)
has been mapped to chromosome 19q13.
Paroxysmal dyskinesia: They occur in the 3rd to 4th decades of life, consisting of different types according to the duration of the attacks. Paroxysmal dyskinesias are often classified into paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal non-kinesigenic dyskinesia (PNKD), based upon precipitating factors that precede or trigger the episodes of abnormal, involuntary movement. In patients with PKD the episodes of hyperkinetic movements are provoked by sudden voluntary movement or unexpected stimuli (startle). In contrast, in those with non-kinesigenic dyskinesia, the attacks may occur spontaneously while at rest or out of a background of normal motor activity, but may be exacerbated by alcohol or caffeine consumption, stress, fatigue, or other factors. Other types of paroxysmal dyskinesias include episodes precipitated by prolonged exertion (paroxysmal exertion-induced dyskinesias, PED) or sleep (paroxysmal hypnogenic dyskinesias, PHD). The most common and best recognized paroxysmal dystonias are paroxysmal kinesigenic dyskinesia (PKD), paroxysmal hypnogenic dyskinesia (PHD) and paroxysmal dystonic non-kinesigenic dyskinesia (PNKD), also know as paroxysmal dystonia. Age at onset can vary between childhood to 40 years. The duration of the attacks is inversely related to the number of attacks (PKD; up to 100/day, PNKD; 2/year-3 day, PHD; 2/year – 5/night). Boys are more affected than girls. Sporadic and autosomal dominant hereditary forms have been described. The attacks are often preceded by a sensory change such as tightness, numbness, pins and needles, or tingling in the affected region. The recurrent, sudden, brief and transient attacks of involuntary movements in PKD and PNKD are often a mixture of chorea, athetosis, dystonia, ballismus, or any combination of these abnormal movements involving muscle groups of the arms, legs, trunk, face, and/or neck and are triggered by various factors such as startle, exercise, anxiety, excitement, caffeine etc. Involvement of facial or oromandibular muscles often results in transient facial grimacing, difficulties speaking (dysarthria), or even muteness; however, important is that consciousness is preserved during the episodes and that the patient is normal between the attacks, which indicates that the diagnosis is based almost entirely on the history. The attacks can even cause the person to fall. In addition to sudden movement, some episodes may also be provoked by unexpected stimuli (startle), yawning, talking, hyperventilation, the anticipation of movement, or light (photic) stimulation. Attacks may be worsened by certain factors, such as stress, cold, heat, or menstruation. PED is primarily characterized by sudden, transient, dystonic attacks, associated with involuntary, repetitive, twisting motions and distorted, often painful posturing. In some patients, attacks of dystonia may be accompanied by irregular jerky movements (chorea) and relatively slow, writhing movements that appear to flow into one another (athetosis). Such episodes are brought on by strenuous activity or prolonged exertion, such as running or walking for approximately 5 to 15 minutes. PHD, which is now generally recognized as a form of frontal lobe epilepsy, is characterized by transient attacks of involuntary movements occurring during non-REM sleep. During PHD attacks, the eyes may open and there may be abnormal, involuntary, potentially violent movements of the arms, legs, and trunk. These may include uncontrollable flinging or throwing movements of the arms and legs (ballismus); excessive rigidity, with associated, repetitive, twisting motions and distorted, potentially painful posturing (dystonia); and irregular jerky motions (chorea) and relatively slow, writhing movements that appear to merge into one another (athetosis). Although patients usually fall asleep after PHD episodes, they typically remember the attacks. Episodes may be worsened by certain factors, such as fatigue, stress, increased activity, or menstruation. PHD attacks may initially occur approximately 4 to 5 times each year. Over time, however, the frequency of episodes may increase up to 4 to 5 times nightly. The attacks are usually relatively brief, ranging from about 20 to 50 seconds or up to approximately 2 minutes.
The loci (e.g. 16p11.2) involved have been identified for some of the paroxysmal dystonias. PNKD gene is mapped to chromosome 2. Linkage data suggest that PHD is a disorder with age-dependent, variable phenotypic expression of abnormal movements as well as generalized or partial seizures. PND is associated with medial frontal lobe epilepsy. PKD responds well to phenytoin, phenobarbital, primidone, valproic acid, acetazolamide and carbamazepine. Clonazepam is often considered the medication of choice for PNKD and PHD. Patients with PED may benefit from clonazepam and the anticonvulsant agent carbamazepine. They need to be differentiated from repeated seizures or epilepsy and hyperexplexia (startle disease), tetany. Symptomatic PKD may also occur in association with MS or perinatal encephalopathy, traumatic brain injury, inflammation of the brain (encephalitis), calcium deposits in the basal ganglia, lack of oxygen supply to brain tissues (anoxia), brief interruptions of blood supply to part of the brain (transient ischemic attacks), brain tumors, and or other underlying disorders or conditions. Symptomatic PNKD may also develop in individuals with acquired immunodeficiency syndrome (AIDS), diabetes or idiopathic hypoparathyroidism.
GM1
gangliosidosis (GM1 ggld):
In chronic (or adult) GM1 ggld, an autosomal recessive disorder
caused by a deficiency of acid
β-galactosidase,
neuronal storage is almost exclusively limited to the basal ganglia. The
disorder may present in the 3rd decade of life with predominantly
extrapyramidal features (dysarthria, gait difficulties, dystonia and parkinsonism).
Dementia is mild, and a cherry-red spot, facial deformity and organomegaly are
not found. Brain MRI reveals putaminal lesions. The diagnosis is based on
reduced
β-galactosidase
activity in peripheral blood lymphocyte. The gene has been mapped to chromosome
3p21.33.
Niemann-Pick disease type C (NPC): This autosomal recessive disorder is almost invariably characterized by two major features: psychomotor retardation and supranuclear downgaze paresis. In addition, ataxia, extrapyramidal features (dystonia) and seizures occur. In late-onset cases progressive dementia or psychosis may be the major presenting manifestation besides supranuclear downgaze paresis, extrapyramidal features and seizures. Unlike in early-onset cases visceromegaly is usually mild. The diagnosis is based on the triad of vertical gaze paresis, organomegaly and foam cells (sea blue histiocytes) in the bone marrow. A confirmatory test is the determination of the rate of cholesterol esterification in cultured skin fibroblasts. The NPCI gene is located on chromosome 18q11-12. Brain MRI is usually normal or may show demyelination. Death usually occurs from aspiration and intercurrent pulmonary infection.
Homocystinuria (hyperhomocysteinemia): Homocystinuria consist of three forms: cystathionine b-synthase deficiency (homocystinuria), defects in methylcobalamin synthesis and deficiency of methylenetetrahydrofolate reductase (MTHFR)(hyperhomocysteinemia without homocystinuria).
Homocystinuria (type I) due to cystathionine b-synthase deficiency is the commonest cause of primary homocystinuria and leads to severe hyperhomocysteinemia. Vascular events remain the major cause of morbidity and mortality in the untreated patients with homocystinuria. Phenotypically this autosomal recessive disease resembles Marfan syndrome with bilateral lens dislocation (ectopia lentis), myopia, glaucoma and marfanoid skeletal deformity, in addition to generalized dystonia. Skeletal changes include scoliosis and osteoporosis. Vascular events early in life are very common: stroke at a young age (30%), myocardial infarction (10%), peripheral arterial occlusion (11%) and peripheral venous occlusion, including pulmonary embolism (51%). Psychiatric symptoms include episodic depression, chronic behavioral problems, obsessive-compulsive behaviors, and personality disorders. Low IQ and seizures occur in 20% of patients. Measurement of urine homocystine, and plasma homocysteine and methionine facilitate the diagnosis. Pyridoxine, is a cofactor for cystathionine b-synthase, and pyridoxine responsiveness found in a subset of patients is based on the presence of small residual activity of cystathionine b-synthase (chromosome 21q22.3).
Mild to moderate homocystinemia (type II) resulting from reduced circulating levels of folic acid, vitamin B12, or vitamin B6.
Homocystinuria (type III) is autosomal recessive and is due to deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR). It is the most common inborn error of folate metabolism. The disease develops usually in the 2nd or 3rd decades of life and is characterized by progressive premature atherosclerosis and recurrent thromboembolic complications with a variety of neurological manifestations (cerebellar ataxia, spastic paraplegia, paresthesia, seizures, and mental dysfunction). Asymptomatic forms have been described. NCVs may be slowed. MRI demonstrated abnormalities characteristic of leukodystrophy. The diagnosis is based on raised plasma total homocysteine (normal <15 micromol/L) and methionine (normal <37 micromol/L) levels. MTHFR activity is low in lymphocytes, leukocytes and cultured fibroblasts. The gene is mapped to chromosome 14q24.
Kufs disease type B (adult neuronal ceroid lipofuscinosis): In adolescence to middle age adulthood, two clinical Kufs phenotypes emerge; type A, featuring progressive myoclonic epilepsy with marked photosensitive and generalized tonic-clonic seizures developing at around the age of 30 years with subsequent ataxia, and dysarthria, dementia, and later pyramidal and extrapyramidal signs. There are no visual problems and seizures are often refractory; and type B, dominated by neuropsychiatric symptoms, including behavioral disturbances and dementia, and may be associated with cerebellar or extrapyramidal signs (cranial dystonia including facial dyskinesias or parkinsonism). The dementia syndrome is characterized by gradual onset, progressive course, and deficits in episodic memory, executive function, and visuospatial abilities; these features and the pattern of cognitive dysfunction thus overlap those of more common neurodegenerative dementing illnesses, including AD. Dementia may be the presenting symptom of Kufs disease and may not be manifested until the seventh decade of life. Unlike other forms of neuronal ceroid-lipofuscinosis, it does not cause blindness. Electrophysiologic and neuroradiologic studies are nonspecific. Giant VEP and large SSEPs can be elicited. Abnormal photic drive (high-amplitude spike at low rates of stimulation) is observed during EEG. Brain MRI may show predominantly cerebellar atrophy and signal changes on T2 in the putamina. The diagnosis is based on the presence of granular osmiophilic deposits found by EM in rectal, muscle, skin or liver biopsy and are deficient in lysosomal palmitoyl protein thioesterase. Urinary sediment dolichol levels are elevated in both types. The disease is autosomal recessive (rarely dominant) and caused by mutation in CLN3 gene of which the locus is unknown. Kufs disease should be considered when seizures and motor disturbances complicate the early course of atypical dementia in middle adult life. Visual loss and optic atrophy are unusual and in combination with the later age at onset clinically distinguished Kufs disease from other NCLs. Mean length of illness is about 7 years.
Propionic acidemia: This autosomal recessive disorder presents in adulthood with chorea, dementia, seizures and episodes of recurrent vomiting (ketosis and acidosis). Plasma, urine and CSF propionic acid levels (organic acids screening) are elevated and excretion of metabolites, including methylcitrate are typical. Propionic acidemia is due to propionyl CoA carboxylase deficiency (chromosome 3q13.3-22).
Mitochondrial disorders such as LHON may present with dystonia.
Basal ganglia calcifications: Elderly, Fahr disease (sporadic or autosomal dominant idiopathic basal ganglia calcification), hyper- and hypoparathyroidism, pseudoparahypoparathyroidism, certain familial disorders (lipodystrophy) and idiopathic forms.
Japanese encephalitis (JE): It is the most common cause of human viral encephalitis worldwide and is caused by a mosquito-born flavivirus. It occurs in epidemics throughout South East Asia, China, the Pacific Rim, India and Australia. Particularly young individuals are affected. The clinical features are those of meningoencephalomyelitis and include nonspecific prodromal stage, followed by headaches, nausea, vomiting, behavioral changes, altered state of consciousness and often seizures. A parkinsonian face-like appearance is a common finding. During the acute phase and convalescent stages, movement abnormalities (parkinsonism and dystonia) are observed which may resolve during recovery over weeks or months. Occasionally polio-like flaccid paralysis may be the presenting feature. Decerebration and decortication may be prominent. MRI lesions may be located in thalami, basal ganglia or substantia nigra. CSF reveals the presence of JE antigen and antibodies. PCR in CSF is the preferred diagnostic test which can be confirmed later on by the presence of anti-JE virus IgM in CSF (sensitivity and specificity over 95%). 40% of survivors have residual neurological deficits. The mortality ranges between 20-40%. A vaccin is available.
SCA-1:
maps to chromosome 6p22-p23 (ataxin-1). The prevalence of SCA-1 is about 3-15%
among ADCAs. Its onset is in the 2nd and 3rd decades.
Ataxia is an early and prominent feature along with optic atrophy, dysphagia and
pyramidal signs with prominent spasticity.
Atrophy and fasciculations may occur late in the facial, lingual and mastication
muscles. Loss of vibration, progressive extrapyramidal features and
ophthalmoplegia (slow saccades) occur less frequently and are often late
manifestations. Axonal sensory or sensorimotor polyneuropathy is found in
42% of patients. There may
be some intellectual decline. Brain MRI shows cerebellar and pontine atrophy. CSF is
normal.
SCA-2:maps to chromosome 12q23-q24.1 (ataxin-2). The prevalence of SCA-2 is about 6-15% among ADCAs. The age of onset is in the 2nd or 3rd decade. The most prominent features are ataxia associated with slow saccades, areflexia and myoclonus. Dystonia and dementia may occur. Lifespan is variably decreased. Axonal sensory or sensorimotor polyneuropathy is found in 80% of SCA-2 patients.
SCA-3
or Machado-Joseph disease
is the most common SCA, accounting for 30-40% of ADCAs. It maps to chromosome
14q24.3-q32 (> 60-84 CAG repeats). Three clinical types of SCA-3 have been
identified: (1) ALS-parkinsonism-dystonia
form: onset before the age of 20 years and presents with limb weakness and spasticity
affecting predominantly the legs and is associated in the majority of patients
with ataxia and extrapyramidal signs (dystonia). Prominent pharyngeal weakness
and spasticity with difficulty of speech and swallowing. Horizontal and vertical
nystagmus, loss of fast saccadic eye movements and impairment of upward gaze.
Peripheral neuropathy may occur. Fasciculations of face and tongue, without
atrophy are common and early features. (2) Ataxic
type: is the most common form. It begins in the 2nd or 4th
decade and consists of progressive cerebellar ataxia followed by pyramidal
and extrapyramidal deficits. As in type I, ophthalmoparesis, upward gaze
deficits, facial and lingual fasciculations are also present. It needs to be
differentiated from OPCA. (3) ataxic-ALS
type: or late onset form (>
50 years) presents with pure cerebellar syndrome, distal sensory loss (all
modalities) and distal amyotrophy (axonal sensory or sensorimotor
polyneuropathy is found in 54% of the SCA-3 patients).
No pyramidal, dementia or extrapyramidal findings occur. Patients are
non-ambulatory within 20 years after onset.
Familial ataxia with vitamin E deficiency (FAVED): Since its phenotype can be indistinguishable from FA, vitamin E estimation may be essential to make the differential diagnosis. The disease is autosomal recessive begins in adolescence and is caused by a mutation of the a-tocopherol transfer protein (a-TPP gene) on chromosome 8q13.1-3. a-TPP incorporates a-tocopherol into lipoproteins secreted by liver. FAVED results in a progressive spinocerebellar syndrome associated with sensory peripheral neuropathy (loss of vibration sense) with absent tendon reflexes, tremor, dystonia (13%), head titubation (28%), deafness, bladder dysfunction and retinitis pigmentosa. Xanthelasmata and tendon xanthomas may be present. Serum reveals very low vitamin E, high cholesterol, triglyceride levels and β-lipoprotein. Acanthocytes can be found in blood smear. Therapy consists of vitamin E supplements 400-1,200 IU/day for life.
Aceruloplasminemia: This autosomal recessive disorder presents in the 4th to 5th decade of life and is caused by a mutation in the ceruloplasmin gene and affects iron metabolism. A triad of cerebellar ataxia, retinal degeneration and diabetes mellitus in a middle-aged person typically characterizes the disorder. Involuntary movements (late-onset blepharospasm) and dementia may occur in later stages of the disease. Heterozygotes are asymptomatic. Serum ceruloplasmin is low, plasma ferroxidase activity is reduced with 60%, while serum iron and transferrin saturation are normal. Plasma copper and ferritin may be increased. CSF analysis reveals threefold increase in iron concentration. Urinary copper may be increased. MRI shows cerebellar atrophy and T2 weighted studies are remarkable for the presence of iron deposition (increased signal intensity in the basal ganglia and thalamus, and dentate nuclei). PET scan shows cortical glucose hypometabolism.
Corticobasal ganglionic degeneration (CBGD): This sporadic degenerative disorder occurs after the age of 60 years and is characterized by a striking asymmetric parkinsonism and localized cortical deficits. The most common signs and symptoms in descending order are: asymmetric limb rigidity (100%), upper limb apraxia (91%), gait difficulties (89%), stimulation-sensitive focal myoclonus (88%), eye movement abnormalities (particularly in later stages supranuclear horizontal or vertical gaze saccadic palsy) (78%), limb dystonia (77%), pyramidal signs (73%), dysarthria (62%), cortical sensory abnormalities (55%), and the "alien limb" phenomenon (55%). Early falling and postural instability are also common. Typically one extremity may be in a dystonic posture and exhibit dyspraxia. The response to levodopa therapy is poor and progression to FTLD is common. Therefore some clinical overlap between CBGD and FTDP and FTLD may occur. The diagnosis of CBGD is ultimately clinical. Neuroimaging of the brain may reveal pontine atrophy and asymmetrical frontoparietal cerebral atrophy corresponding to the symptomatic side in about 50% of cases, whereas atrophy is symmetric in the other 50%. The prognosis is poor with an average survival rate of 5 - 10 years. Differential diagnosis should include levodopa responsive parkinsonism, ataxia, and progressive myoclonic epilepsy, AD, PSP, MSA, hemiparkinsonism, and FTDP and FTLD.
Wilson disease (WD): The prevalence of the disease is around 1/100,000 in the general population. Early onset (2nd to 3rd decade of life) or atypical parkinsonism (particularly affecting the bulbar musculature) in the presence of liver dysfunction or psychiatric abnormality should suspect WD. Alternative clinical presentations may be the dystonic or cerebellar form. Dysarthria, sialorrhea and personality change, gait abnormalities and arm tremor account for the majority of presenting symptoms and signs. The diagnosis is based on the triad of Kayser-Fleischer ring (slit lamp examination), low serum ceruloplasmin (levels are low in 90% to 95% of individuals with WD, but can also be low in asymptomatic carriers or can be normal in 5-10% of patients with the disease) and elevated 24-h urinary copper excretion (best confirmatory test; if greater than 100 mg/24 hours, levels < 50 mg/24 hours rules out WD). Since false positive or negative tests occur liver biopsy will settle the matter (copper levels exceeding 250 mg/g dry weight are diagnostic). Kayser-Fleischer ring is present in all patients with neurologic or psychiatric disease and its presence may antedate overt symptoms of the disease. There is no correlation between the degree of brain pathology and the clinical presentation. Brain MRI is usually abnormal in those with neurologic or psychiatric disease, but may be completely normal in those with pure liver disease. MRI may show increased signal in the midbrain (“face of the giant panda”), basal ganglia, ventrolateral thalami, posterior limb of the internal capsule, or middle and superior cerebellar peduncles on T2 and proton-dense images but are not specific. The disorder is autosomal recessive and the gene mutation has been mapped to chromosome 13q14.3, which encodes for a copper transporting P-type ATPase (ATP7B protein). However there are a large number of mutations which can make the diagnosis impractical, unless a gene abnormality has been established in a given family. Slit lamp examination, serum ceruloplasmin and liver function tests are useful in screening of siblings at risk. Penicillamine is clearly efficacious, but it has many potential side effects: it can cause hypersensitivity reactions, induces the production of autoantibodies, which can ultimately lead to Goodpasture disease, MG, or lupus. Pyridoxine should be added to prevent anemia. The most worrisome side effect is the precipitant worsening in a patient's neurologic status after initiating penicillamine therapy. Up to 50% of patients with neurologic WD have sudden neurologic worsening. Of those, 50% experience permanent disability that is more severe than their clinical status when penicillamine was initiated. Any disability that persists 2 years after starting therapy will probably be permanent. However, the brain MRI may continue to show improvement for up to 4 years after therapy is initiated. Differential diagnosis which should always be considered are HD, HSD, neuroacanthocytosis, mitochondrial cytopathy, and a rare familial disorder called aceruloplasminemia.
Subacute necrotizing encephalopathy (SNE) or Leigh disease: Several synonyms exist such as Leigh necrotizing encephalopathy, Leigh syndrome and necrotizing encephalomyelopathy of Leigh. Adult-onset forms of SNE are sporadic, or inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial trait. To complicate matters even more several different types of genetically determined enzyme defects can cause SNE. As with other mitochondrial disorders, the onset of neurologic symptoms present from the 1st - 6th decade with acute or subacute onset, often precipitated by surgical intervention or febrile illness. The disease can present with a variety of symptoms such as brainstem dysfunction (central respiratory failure, intermittent oculomotor palsy, cranial nerve dysfunction including deafness, optic atrophy or Wernicke-like syndrome), ataxia, or extrapyramidal (dystonia) symptoms, global cognitive dysfunction (dementia or mental retardation (30%)), spastic paresis, myoclonic jerks and seizures, peripheral demyelinating polyneuropathy, motor decline and unconsciousness with lactic acidosis. In addition, insulin-resistant diabetes mellitus, muscular weakness, intractable nausea and vomiting, and anemia can occur. The disease can be intermittent progressive or remitting/relapsing. CSF protein may be increased. Brain MRI shows abnormal high intensities in basal ganglia, particularly putamen, on T2 weighted images, bilateral medial regions of the thalamus, brainstem and periaqueductal gray matters. Proton MRS may show elevated lactate level in involved regions of the brain. Ragged red fibers can be found on muscle biopsy with increased succinic dehydrogenase activity and cytochrome oxidase negative fibres in almost 90% of cases. Pre- and postprandial serum and CSF lactate and pyruvate are useful in the diagnosis. Serum lactate is increased in 50% of patients but is less sensitive than CSF lactate. Pyruvate dehydrogenase deficiency (or Lactic and Pyruvate Acidemia with Episodic Ataxia and Weakness) presents with episodic ataxia, seizures, and hypoglycemic episodes and may mimic SNE. Serum and urine amino acid analyses reveal hyperalaninemia. Treatment for SNE is empirical but the administration of thiamine, coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.
Panthotenate kinase-associated neurodegeneration or Hallervorden-Spatz disease (HSD): The adult onset form of this autosomal recessive disorder presents in early adulthood with atypical parkinsonism (initially affecting the legs or bulbar musculature), ataxia, myoclonus, dystonia (tongue or blepharospams), chorea or dementia. Most patients also develop pyramidal syndrome and seizures (20%). T2 weighted brain MRI shows an ”eye of the tiger” sign corresponding to pallidal hypointensity with a high signal center. Very low signal intensity is also seen in the red nucleus, and substantia nigra, consistent with increased iron deposition in these structures. Bone marrow contains sea blue histiocytes. The gene locus (PANK2) has been identified on chromosome 20. Treatment of patients with HSD is largely symptomatic. Many patients, especially in the early stages of the disease, may respond modestly to levodopa treatment. Variants have been reported such as HARP syndrome (hypoprebetalipoproteinemia [very low VLDL], acanthocytosis, retinitis pigmentosa, and pallidal degeneration). The dystonia affects cranial musculature and MRI findings are those of HSD. HSD needs to be differentiated from WD, juvenile HD, SNE, PD, DRD, Fahr disease, Lafora body disease (EPM2), MS, DRPLA, Kufs disease, gangliosidoses and APBD.
Subacute sclerosing panencephalitis (SSPE): SSPE is a neurodegenerative disease due to persistent rubeola (measles) infection that affects children and young adults. Onset of the disease is insidious and often only recognized after significant neurologic deficits occur. The diagnosis of SSPE can be made if three of the following five criteria are fulfilled: 1) typical clinical presentation with progressive cognitive decline and stereotypical myoclonus (sustained myoclonus), 2) characteristic EEG changes, 3) elevated cerebrospinal fluid globulin levels without pleocytosis, 4) elevated CSF measles antibody titers, and 5) typical histopathologic findings in a brain biopsy or autopsy. Affected individuals progress through four loosely defined clinical stages at differing rates. Stage I is characterized by subtle behavioral changes, cognitive decline, emotional lability, lethargy, and nonspecific neurologic symptoms. This stage may last for weeks to months. Stage II includes continued intellectual decline, myoclonus, focal seizures with secondary generalization, choreoathetosis, apraxia, and visual changes with optic atrophy, dysarthria, and tremors. A wide variety of visual disorders have been associated with SSPE, including papilledema, retinitis, chorioretinitis, optic nerve pallor, homonymous visual field deficits, and cortical blindness. This stage may last three months or less. Neurologic decline persists in stage III (decreased level of consciousness, autonomic instability (with a variable heart rate and widely fluctuating temperatures and blood pressures), dystonia and rigidity, decorticate/decerebrate posturing), but the pace slows down, and symptoms may stabilize for one to two years. Features of stage IV include active startle reflex, flexor limb positioning, quadraparesis, akinetic mutism, wandering eye movements and coma. At this time, myoclonus, seizures, and rigidity are less frequent than in prior stages. CSF reveals markedly elevated intrathecal IgG synthesis rate and multiple oligoclonal bands in the gamma region on high-resolution electrophoresis, without a cellular reaction. Serum and CSF rubeola IgG titers are elevated with normal IgM titers. The EEG exhibits periodic complexes with generalized bilateral, usually synchronous and symmetrical sharp and slow wave complexes of high amplitude (greater than 500 uV), classically occurring every 5-10 seconds. Early in the course of the disease these periodic discharges may occur on a normal background but later the background becomes increasingly slower and disrupted. These periodic complexes are usually associated with clinically evident myoclonic or dystonic activity. MRI may be normal or may show early changes of increased signal on T2-weighted sequences, frequently involving the periventricular or subcortical white matter in the frontal, temporal, and occipital white matter; late changes include significant white matter loss, approximately 30% of patients show basal ganglia changes, while 25% have cortical changes. Fifty percent of patients who develop SSPE had measles (rubeola) before two years of age, and 80% before age four years. Five percent of patients survive three months or less and 20% survive four or more years, with a mean survival of only 18 months. Death occurs in stage IV, often the result of intercurrent illnesses such as pneumonia. MS (visual changes, oligoclonal bands) is often considered in the differential diagnosis of SSPE. Treatment is disappointing. The most promising results to date have used a combination of inosiplex, an antiviral agent, and intraventricular or intrathecal alpha-interferon as an immunomodulator, with stabilization or improvement in some patients. Early childhood measles vaccinations remain critical in limiting the incidence of SSPE.
Spastic paraplegia, ataxia, mental retardation (SPAR): This autosomal dominant disorder is characterized by either pure spastic paraplegia, spastic ataxia, spastic ataxia with mental retardation and dystonia. MRI shows cerebellar atrophy. It needs to be differentiated from SCA-1-3, 6-8 and 12, DRPLA and HSP.