Akinetic-rigid syndrome


Drugs-induced parkinsonism: Drugs such as neuroleptic agents including metoclopramide, α-methyldopa, lithium, flunarizine and selective serotonin reuptake inhibitors are known to induce parkinsonism. Drug withdrawal relieves symptoms but may require weeks or months. The frequency of neuroleptic-induced parkinsonism is at least 15%. Drug-induced parkinsonism has often been considered to occur in patients with subclinical PD.

Toxin-induced parkinsonism: Several toxins can induce parkinsonism including; ethanol, carbon monoxide (in addition to dystonia, mental changes, mutism and spasticity), carbon disulfide, mercury, methanol, MPTP and cyanide. Manganese occurs during occupational exposure (mining and steel alloy-welding). Manganese dust and fumes are responsible for most of industrially associated manganese toxicity. In a first phase, the patient may complain of subjective symptoms of headache, nervousness, and mental slowing, together with occasional bursts of agitation and hallucinations. This is then followed by parkinsonism with prominent dystonia especially involving gait. Lack of tremor, psychiatric symptoms and levodopa-responsiveness are often helpful in the diagnosis. Brain MRI shows typically abnormal increased signal bilateral in the globus pallidus on T1-weighted sequences (differential diagnosis include liver disease and parenteral nutrition). The diagnosis is supported by demonstrating high manganese levels in serum and urine. Successful treatment of human manganism is only possible in the early phases of the disease. Withdrawal of exposure is mandatory. Response to levodopa is very limited and tends to be transient. The most important manganese mines are found in Brazil, India, Congo, Gabon, Ghana, South Africa and USA.

Post-traumatic parkinsonism: Chronic traumatic encephalopathy (dementia pugilistica) as seen in boxers is an example of post-traumatic parkinsonism. Other neurological features may be present and the response to levodopa may be variable. Neuroimaging may show a cavum septum pellucidum and cerebral atrophy.

Idiopathic Parkinson disease (IPD): About 1% of the population over the age of 65 years develops IPD. The peak age of onset is in the 6th decade of life. The diagnostic criteria include bradykinesia plus one of the following: rigidity, resting tremor or postural instability. The onset is often asymmetric and decreased blinking and facial expression are often the first signs. IPD differs from other forms of parkinsonism by a significant and sustained (>5 years) response to levodopa. Despite this, levodopa challenge is generally an unreliable discriminator of IPD. Resting tremor and choreiform levodopa-induced dyskinesia, usually affecting the limbs, are useful clinical signs when present. Autonomic failure and predominantly dementia  (30%) may develop as the disease progresses. Camptocormia (bent spine syndrome) most prominent in thoracolumbar spine but also expresses as head drop syndrome presents in walking position and typically abating in the recumbent position. injections of botox in abdominal rectus muscle may be useful. Early-onset IPD differs from classical IPD by its early onset (3rd decade) and high incidence of lower limb dystonia (painful foot inversion) in untreated patients. The response to levodopa is good but there is a high tendency for developing motor response fluctuations and dyskinesias. The progression is slower than in classical IPD. A positive family history is common and often referred to as genetic PD. Mutation in the parkin gene at chromosome 6q25 have been found in many patients with early-onset autosomal recessive PD (particularly juvenile PD which occurs before the age of 20 years). Other rare mutations are α-synuclein (4q21-23), PTEN-induced putative kinase 1, oncogene DJ-1, leucine-rich repeat kinase 2 (LRRK2), UCHL1, and gene loci on a variety of chromosomes. Critical in early-onset IPD is the issue that these patients do not develop Lewy bodies and hence do not fulfill the criteria for IPD. Finally, it is noteworthy that even in the best Movement Disorder clinics from 10-35% of patients initially diagnosed with IPD will actually turn out to have a “Parkinson Plus” syndrome. Brain MRI in IPD may reveal patchy signal loss of the substantia nigra. Treatment with levodopa/carbidopa remains the mainstay in early and advanced IPD. It improves quality of life more than therapy with dopamine agonists. However to avoid motor response fluctuations concomitant dopamine agonist therapy (pramipexole, ropinirole) is indicated in the early phase of the disease. In advanced PD, bilateral subthalamic nucleus stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms.

Multiple system atrophy (MSA): MSA, also called "Parkinson Plus” syndrome, is estimated at 0.04 in the general population. The mean age of MSA onset is 52.5 years ranging from 30 to 70 years and consists of the following clinical subtypes: MSA-P (predominantly parkinsonism) and MSA-C (predominantly cerebellar ataxia) however the predominance can change over time. Varying degree of parkinsonism and autonomic dysfunction (urogenital dysfunction and orthostatic hypotension) are the common and prominent initial clinical manifestations of MSA. Later on followed by cerebellar ataxia (49%) and pyramidal involvement (61%). There is no clinical feature that clearly distinguishes MSA-P from IPD, but tremor is less prominent, response to levodopa therapy is poor, and cervical dystonia (anterocollis) is more prominent in the former. The extremities are dusky (violet in appearance indicating autonomic dysfunction), the voice is squeaky, there is early hand dystonia and ocular dysmetria (overshoot). Furthermore the clinical features of MSA in general are governed by rapid progressive asymmetrical limb rigidity with bradykinesia and jerky postural, intention tremor or no tremor at all. Other clinical signs include early falling and fine myoclonic jerks of the fingers/limb and can be elicited by tapping the limb. The cerebellar syndrome is usually subtle with gait and limb ataxia, nystagmus and dysarthria. Similarly, pyramidal signs are also subtle e.g. increased tendon reflexes, extensor plantar response, pseudobulbar syndrome, or mild spasticity. Autonomic dysfunction consists of orthostatic hypotension (68%), urgency and frequency of micturition (55%) or impotence (80%) prior to the start of levodopa therapy. Other signs may include respiratory irregularities (inspiratory stridor), severe antecollis (“sunflower” appearance or also called camptocormia) and sometimes mild eye movement and REM sleep abnormalities. Dementia occurs rarely. Ancillary investigations for MSA should include autonomic function tests, brain MRI and external urethral and anal sphincter EMG (false positive for PSP).  Reduced striatal 131I-iodobenzamide binding is suggestive for MSA and has successfully predicted levodopa responsiveness. In MSA, there is little (30-50% of patients respond) or short-lived response (1-2 years) to levodopa and atypical orofacial levodopa-induced dyskinesias rapidly develop. MSA should be differentiated from ILOCA and hereditary late-onset SCA, by the presence of autonomic impairment and lack of family history. Progressive autonomic failure (PAF) differs from MSA by the slower onset and progression, absence of associated neurological features, no REM sleep abnormalities, no syncope or postprandial hypotension. Furthermore in PAF, autonomic function tests indicate peripheral autonomic dysfunction. In contrast to PSP, no ophthalmoplegia is observed. On T2 weighted MRI of the brain, in MSA-P the putamen shows reduced signal running up the lateral extent (increased iron deposition) and this may be covered by a rim of increased signal. If there is associated MSA-C the lateral as well as longitudinal pontine fibers become evident as high signal (“hot cross bun” sign = cross-shaped T2 signal hyperintensity within the pons) and pontine or cerebellar atrophy may also be present. The disease progression of MSA is abnormally rapid and median survival is about 10 years.

Progressive supranuclear palsy (PSP): The prevalence of PSP is approximately 1.4/100,000. The disease can be sporadic or autosomal dominant, and usually occurs after the age of 40 years. This progressive degenerative disorder’s key features are early gait instability and backwards falling (within a year of onset) and supranuclear downgaze palsy (often a late feature or even absent). First, pursuit in the vertical direction and early slow vertical saccades, particularly downward impairment. Attenuated response to vertical optokinetic nystagmus. Difficulty in reading is often the first manifestation. Doll’s head maneuver remains intact vertically, indicating that the nuclear and infranuclear mechanisms for upward gaze are intact and that the defect is supranuclear. Bell’s phenomenon remains intact bilaterally. In addition, early pseudobulbar signs (nasal spastic dysarthria, robotic dysphonia and dysphagia), axial rigidity, mild pyramidal signs, blepharospasm, eyelid opening apraxia, ptosis is followed by symmetric parkinsonism without tremor. A striking clinical feature is the frozen staring expression with reduced blinking, frontalis overaction (preceros sign) and fixed gaze (“scary or angry face” appearance). In addition there are frontal signs and there is mental impairment with inability to interpret proverbs. Total sleep time and REM sleep decreases. Poor response to levodopa therapy (rigidity and bradykinesia may respond, but axial dystonia and ophthalmoplegia are not affected) and progression to frontal lobe dementia are common. None of the laboratory or radiologic investigations are contributory, but are important to rule out other conditions. Tau 33kDa/55kDa ratio in the CSF is reduced in PSP. In late stages brain MRI may reveal atrophy of the midbrain (“mouse ears” sign). The diagnosis is initially often missed and the patient is labeled, as IPD patient until eye movement abnormalities occur. Familial forms are associated with mutations of the tau gene on chromosome 17. The median survival of patients with PSP is about 6 years.

Lewy body disease (LBD): The disease is more common in men than women with a ratio of 2:1. The mean age at onset of symptoms is around 70 years. The diagnostic criteria for LBD are at least one of the following: 1) early fluctuating mental state with episodic delirium, 2) prominent psychiatric symptoms such as depression, florid visual and/or auditory hallucinations (recurrent and detailed; involves animals and people) and paranoid ideation and 3) strikingly asymmetric extrapyramidal syndrome (parkinsonism often only gait abnormalities with postural instability, lack of tremor) spontaneously or associated with neuroleptic therapy. Secondary features are: repeated falls, syncope and transient loss of consciousness, high-sensitivity to neuroleptic drugs (e.g. persistence of parkinsonism after discontinuation of neuroleptic therapy), delusions and non-visual hallucinations.  Dementia is the major feature with poor memory often being the initial sign, and often precedes, follows, or coexists with parkinsonism. Sometimes dementia is the only clinical feature. Rare clinical features are limb myoclonus and supranuclear gaze palsy. LBD progresses faster than AD. There is generally little response to levodopa therapy. LBD represents 15 - 30% of all cases of dementia at autopsy. These clinical criteria, when compared with the reference standard of autopsy, have been found to be highly specific (79-100%) but to lack sensitivity (22-75%), implying that these criteria are useful for confirming the diagnosis but cannot be relied on for screening. The differential diagnosis is difficult particularly in those patients with “typical levodopa responsive IPD for years” who then develop confusion and hallucinations, or atypical cases with myoclonus (differential diagnosis with CJD) or supranuclear gaze palsy (differential diagnosis with PSP), and should be suspected in patients with dopaminergic therapy exacerbated confusion and neuroleptic-induced parkinsonism. Diagnosis is often made at autopsy! Biopsy differences from AD in that: ubiquitin-positive neurites in hippocampus are found and with no neurofibrillary tangles in cortex. The average time from onset to death is 6.4 years, with the most frequent cause of death being aspiration pneumonia.

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%), focal myoclonus elicited by stimulation (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.

Alzheimer disease (AD): 50-80% of all dementias are due to AD. About 120 people per 100,000 population is affected by AD annually. The onset of symptoms usually begins after the age of 65 years. Familial AD is autosomal dominant and is the most common form of early onset (presenile) familial dementia. Early signs are deficits in attention, concentration, orientation, abstract reasoning, progressive amnesia (often periodic loss of recent memory e.g. delayed verbal recall rather than remote memory). As the disease advances problems with language (impaired naming, progress to fluent aphasia, and mutism), calculations, topographical memory and visuospatial functions (difficulty driving, getting lost, difficulty copying figures) and praxis (constructional dyspraxia) become increasingly apparent. Parietal signs typically appear after memory loss. Behavioral alterations (depression, agitation, delusions, anxiety and hallucinations) may become evident at any time during the course of illness, but are often precipitated by events such as admission. In contrast to FTLD, language and social functioning are generally preserved until late in the course. Seizures (generalized onset) occur in less than 15% of patients. Extrapyramidal signs occurs in 25% of AD patients. Other manifestations include gait disturbances, frontal signs and  myoclonus (more common in familial forms). The Addenbrooke Cognitive Examination (Neurology 2000;55:1613) is a brief and reliable bedside instrument for early detection of AD, and offers a simple objective index to differentiate AD and FTLD in mildly demented patients. Diagnosis of AD is confirmed at autopsy! Autopsy-confirmation of clinically diagnosed series of probable AD patients is less than 85%. Brain MRI shows atrophy of the hippocampus which correlates with the degree of impaired memory function. APOE e4 allele (chromosome 19) which is more prevalent among AD patients than among the general population, is a risk factor for developing AD and lowers the age of onset of the disease, particularly it makes the late-onset form of AD occur earlier. APOE e4 is found in familial (80%) and sporadic forms (64%) of AD, compared with 31% of controls. Conversely, bearing an APOE e2 allele is associated with a reduced risk for developing AD. The positive predictive value of APOE e4 genotype increases the clinical accuracy 0f 60-70% to almost 100%. In familial forms mutations in presenilin-1 (mapped to chromosome 14q24.3), presenilin-2 (mapped to chromosome 1q31-42) and amyloid precursor protein genes (mapped to chromosome 21q21.1) have been identified.

Creutzfeldt-Jacob disease (CJD): The annual incidence of this prion disorder is 1/million in the general population, 90% being sporadic. Libyan Jews, North African immigrants to France and Slovakians have a higher incidence of developing the disease. Infected corneal transplants, deep brain electrodes, dural grafts and growth hormone preparations have been causes of transmission. The peak age of onset ranges from 55 to 75 years of age. The clinical diagnostic criteria for CJD are: rapidly progressive dementia (confusion, hallucinations, delusions, agitation, changes in visual perception)(<2 years) with periodic sharp wave complexes in the EEG in addition to two of the following: stimulus-sensitive myoclonus (startle reactions), ataxia or visual symptoms, parkinsonism or pyramidal signs, or akinetic mutism. Associated findings are weight loss, anorexia and insomnia. There is paucity of lab abnormalities: CSF may show elevated protein (around 100 mg/dl) and up to 20% of patients may have oligoclonal bands on CSF electrophoresis. CSF 14-3-3 immunoblotting (sensitivity 94%, specificity 84-97%) and tau-protein ELISA (Innogenetics, Ghent, Belgium) (sensitivity 94%, specificity 90%) are positive predictors in over 90% in CJD. EEG findings may be normal or reveal only slowing of background activity, especially early in the course of disease. Initially non-specific changes are observed but later on bilateral synchronous high voltage periodic triphasic sharp wave complexes 0.5 - 2 Hz (sensitivity 67%, specificity 74-86%) are seen. However, the absence of these sharp wave complexes does not rule out the diagnosis of CJD. Brain MRI shows symmetric hyperintense abnormalities in putamen, thalamus and cortex (gyral swelling) on T2 images, which may be supportive for the diagnosis. On T1 images these lesions remain isointense and do not enhance after contrast. FLAIR sequences are preferred, as they may show hyperintense areas of gray matter, particularly in the cerebral cortex, not otherwise appreciated on conventional T2-weighted images. Diffusion-weighted MRI scans may suggest that abnormal cortical signal results from intracellular edema or cytotoxicity. Olfactory (and brain) biopsy may provide diagnostic information in living patients (the conversion of a normal cellular protein (PrPC) to an abnormal isoform, PrPSC). Mean interval between onset and death is 8 months. Precautions should be taken when handling all body fluids of an infected patient, especially spinal fluid. Gloves should be worn during procedures (e.g. lumbar puncture) and accidental skin contamination should be rinsed with a 1:10 dilution of sodium hypochlorite (household bleach). Specimens from known or suspected infected patients should be marked as such, so that laboratories may handle and dispose of them appropriately. Several clinical variants have been described e.g. Heidenhaim variant (typically associated with florid visual hallucinations and cortical blindness), Brownell-Oppenheimer variant (predominantly cerebellar ataxia with little cognitive involvement) and Stern-Garcia variant (predominantly basal ganglia and thalamic form).

Vascular parkinsonism: Multi-infarct syndrome, Binswanger disease and CAA can result in parkinsonism. This form of parkinsonism distinguishes from PD by a prominent wide based parkinsonian gait without parkinsonian signs in the upper part of the body (“lower half parkinsonism”). There is no festination or resting tremor and arm swings are normal, and there is no response to levodopa. Postmortem studies revealed that 3% of IPD patients may have vascular parkinsonism. CAA often causes recurrent lobar intracerebral hemorrhages without other definite causes and is often found in elderly patients with atrial fibrillation on long-term anticoagulant therapy. In contrast to IPD, MRI shows extensive multiple white matter lesions (either infarctions or hemorrhages).

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, subacute 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 to 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 (dementia or mental retardation 30% of patients), 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. Pyruvate dehydrogenase deficiency which is autosomal recessive presents with episodic ataxia, seizures, and hypoglycemic episodes. 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 fibers 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. Treatment for SNE is empirical but the administration of thiamine, vitamin B1, Coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.

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).

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 blepharospasm), 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.

Hemiparkinsonism-hemiatrophy (HPHA): Unilateral parkinsonism with a variable degree of ipsilateral atrophy (often focal hands or face) are the characteristics of this disorder. Brain CT scan may show contralateral cerebral atrophy. The response to levodopa is variable and the progression is slow. Mutations in parkin gene have been reported.

Normal pressure hydrocephalus (NPH): Frontal lobe dementia, urinary incontinence and frontal ataxia (triad of Hakim-Adams) are the clinical characteristics of NPH. Gait disturbance and urinary incontinence usually occurs before dementia develops. The gait disorder is similar to that seen in vascular parkinsonism. A spinal tap can often be diagnostic and therapeutic: 40 - 50 ml of CSF is tapped, and walking and mental function is measured before and after the lumbar puncture. Alternatively, the Katzman test can be used. The Diamox test is not useful. The finding of more than 50% B-waves on intracranial pressure measurement is suggestive of NPH. MRI may show flow void over the aquaduct. High concentrations of sulphatide have also been supportive for the diagnosis. Causes of NPH are SAH, resolved acute or chronic meningitis, Paget disease of the skull base and mucopolysaccharidosis. During shunting it should be aimed for  a pressure of 70 - 90 mm H2O. Major improvement is generally observed during the first 3 months - 1 year after shunting, with gait first improving followed by mental function and last, the incontinence. The complications of shunting are infections, seizures and subdural hematoma and hygroma.

Adult polyglucosan body disease (APBD): APBD is an autosomal recessive disorder. The disease is more common in a subgroup of patients of Ashkenazi Jewish origin. It represents an allelic variant of glycogen storage disease type IV and Lafora body disease (EPM2), and contrary to infantile cases (Andersen disease or type IV glycogenosis or amylopectinosis) is usually not associated with a significant deficiency of the branching enzyme. The disease is caused by mutations of the gene coding for the glycogen-branching enzyme (GBE gene), which is essential for branching of polyglucose chains in the normal glycogen molecule. The age of onset is mostly between 40 - 60 years and its course is slowly progressive. This disorder is recognized by sensory loss in the lower extremities with peripheral neuropathy, chorea, atypical progressive upper and lower motor neuron disease, spastic tetraparesis, parkinsonism unresponsive to dopaminergic therapy, frontal dementia, and bowel and bladder dysfunction. Sural nerve biopsy reveals diagnostic intra-axonal polyglucosan bodies. Similarly the diagnosis of APBD can be confirmed by a skin biopsy from axillary dermal sweat glands showing inclusions in myoepithelial cells of apocrine glands. Decreased glycogen-branching enzyme (GBE) activity in leukocytes can be found. Brain MRI findings reveal cortical atrophy, extensive white matter signal changes on T2-weighted images and/or marked atrophy of the entire spinal cord, without signal abnormalities on long TR images. The disease is often misdiagnosed as adrenoleukodystrophy.

Hereditary spinocerebellar ataxia (SCA) type 1 and 3: SCA formerly called autosomal dominant cerebellar ataxia (ADCA), has a prevalence of 1-5/100,000 in the general population. There is substantial geographical distribution of the different forms of SCA: e.g. SCA-3 is very prominent in Portuguese/Azorean and Dutch families. In contrast to autosomal recessive ataxias, SCA almost consistently develop after the age of 25 years. These SCAs share the primary clinical features of cerebellar syndrome with additionally supranuclear ophthalmoplegia, slow eye movements, optic neuropathy, subcortical dementia, extrapyramidal deficits, dysphagia, pyramidal signs, amyotrophy and peripheral neuropathy. On clinical criteria alone, they are often indistinguishable and one patient would fit to different categories. The classification of ADCA based on clinical and neuropathologic features was therefore used and divided ADCAs into three different groups (ADCA I-III) based on associated signs.

SCA-1 and -3 can be allocated to ADCA I being: progressive cerebellar gait and limb ataxia with pyramidal and extrapyramidal involvement, slow saccadic eye movements, supranuclear ophthalmoplegia, hyporeflexia and dementia. Onset in 4th decade of life and disease duration of 15 years. The progression is slow, relatively symmetric over 15 years or more. The diagnostic issue can be settled by DNA testing (http://www.geneclinics.org). In patients with SCA-1 and -3 there is a high number of CAG trinucleotide repeats (>40) with the length of the expanded repeat being inversely correlated with age at onset. Variable degree of cerebellar and brainstem atrophy may be found on neuroimaging. Clinical properties of the SCAs: 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-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.

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.

X-linked dystonia-parkinsonism (Lubag): Lubag or Filipino X-linked dystonia typically presents with either pure dystonia (that inevitably becomes generalized) or combined dystonia-parkinsonism. It occurs on the Philippine island of Panay and usually develops in the 4th decade with cranial (including larynx/stridor) and limb dystonia or at onset with shuffling and drooling. The DYT3 gene is located at Xq13.1 chromosome.

Rapid-onset dystonia-parkinsonism (RDP): The disorder is autosomal dominant, generally occurring 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.

Huntington disease (HD): The prevalence of HD is around 50/106 in the population from Western European descent. HD is characterized by the triad of autosomal dominant inheritance, choreoathetosis and subcortical dementia. On average the disease starts at the age of 40 years. Chorea (“clumsiness, fidgety”, tongue 'akathisia') is the presenting manifestation in 2/3 of patients while the remainder present with personality or cognitive changes, weight loss, dysarthria, dysphagia or gait disturbance. Changes in oculomotor control (delays in initiation, increased blinking frequency and slowing of saccadic eye movements) may also be an early sign. The disease progresses with rigidity, bradykinesia and eventually immobility. In contrast with early onset HD, in late onset (>60 years) HD, chorea is the prominent feature and runs a milder course. HD must be considered in chorea presenting in pregnancy or taking oral contraceptives. Brain MRI reveals high signal in the putamen, accompanied by symmetric caudate (increased bicaudate-cranial ratio) and putaminal atrophy in clinically affected patients. The latter is a more sensitive marker for early HD. Juvenile HD (Westphal variant) (< 20 years) resembles the rigid variant with additional features of seizures and cerebellar findings. HD is caused by an unstable (CAG)n trinucleotide repeat (n>37-40) in the IT-15 gene on chromosome 4p16.3 encoding for huntingtin. The diagnosis is based on DNA analysis of a blood sample. PET scan shows decreased glucose metabolism in the caudate nucleus early in the disease and precedes the loss of tissue. The survival is variable, but death usually occurs 15-20 years after onset of motor symptoms. Wilson disease should be specifically excluded. Late-onset cases may be misdiagnosed as AD.

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.

Post-infectious parkinsonism: Infectious causes may include Japanese B virus encephalitis, EEE, HIV, syphilis, and SSPE.

Frontotemporal dementia with parkinsonism (FTDP-17): This type of dementia is characterized by early personality change with inappropriate behavior (withdrawal, lack of insight, and desinhibition) and social conduct. Speech and language problems are common, and patients show aspontaneity and stereotypes of speech and can develop mutism.  Memory remains relatively spared. Extrapyramidal features are common (e.g. 40% of patients have parkinsonism): akinesia, rigidity and gait problems occur most frequently, whereas tremor is less common and if present is typically postural. Seizures may also occur. Mutations in tau gene on chromosome 17q21.2 have been found.

Neuroacanthocytosis: The neuroacanthosis exists of three major groups: 1) the core neuroacanthosis syndromes with neurodegeneration of the basal ganglia, comprising autosomal recessive chorea-acanthosis due to mutation of VPS13A (chromosome 9q21) and the X-linked McLeod phenotype (indistinguishable phenotypes) due to mutation of XK gene, 2) conditions with decreased lipoproteins (abetalipoproteinemia and hypobetalipoproteinemia) consisting of peripheral neuropathy and ataxia without movement disorders, 3) associated forms such as HSD (PANK2) and HD (HDL2). The core neuroacanthosis affects men twice as common as women. Symptoms usually start in the 3rd to 5th decade (mean 32 years) and consist of limb chorea, especially affecting the legs, along with parkinsonism, oro-facial dyskinesias, self-mutilation, and dementia. 50% of cases have seizures, areflexia (chronic axonal motor polyneuropathy: small SNAPs; normal CMAPs) with distal symmetric wasting. Elevated serum CK levels and acanthocytes on a fresh wet blood film facilitate the diagnosis. The latter usually precedes the neurologic features. Needs to be differentiated from abetalipoproteinemia (abnormal serum lipoprotein profile) and McLeod syndrome (reduced expression of Kell blood group on RBC and Kx surface antigen (100%)). Brain MRI may show caudate atrophy. Acanthocytes are seen in the peripheral blood smears of some of the asymptomatic family members. Average life span is approximately 14 years from onset of illness.

Dentatorubropallidoluysian atrophy (DRPLA): Although described chiefly in Japan, European families are also affected by this autosomal dominant condition. It is caused by a CAG repeat expansion mutation of atrophin 1 gene mapped to chromosome 12p13 (Boston University Center, Human Genetics Laboratories).  The age of onset of symptoms ranges from adolescence to the 6th decade of life and the presentation is quite heterogeneous. Three phenotypes have been described the ataxo-choreoathetoid type, a pseudo-Huntington type, and a myoclonic epileptic type. Hence clinical features include progressive cerebellar ataxia, or dementia with chorea, or prominent chorea and dystonia or progressive myoclonic epilepsy. Variants (Haw-River syndrome) of the disease exist (subcortical demyelination; neuroaxonal dystrophy; no seizures). Brain MRI scan shows cerebellar and brainstem atrophy and multiple WMHIs on T2 sequences. DNA analysis is essential for the diagnosis. Homozygotes for DRPLA genes may have recessive predominantly spinal syndrome which has its onset in the 3rd or 4th decade and consists of spastic paraplegia, loss of vibratory in the lower limbs and truncal ataxia. In view of its resemblance DRPLA is often confused with HD.

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.