Motor neuron disease


Toxic motor neuron disease (MND): Lead, mercury and aluminum toxicity may present as MND.


Adult-onset amyotrophic lateral sclerosis (ALS): The prevalence of ALS ranges from 4-6/100,000. Sporadic ALS accounts for 90% of cases, whereas autosomal form accounts for the remaining 5-10%. The onset can occur at any age in adult life, but most patients are more over 50 years of age. Typically, the disease begins distal, asymmetric and focal, and then spreads in an anatomic pattern. Initial features are either those of dysfunction of the lower motor neuron (fatigue, weakness of distal limb muscles e.g. drop foot, muscle atrophy e.g. wasted small hand muscles (difficulty with buttons and key manipulation), fasciculations, stiffness in the fingers and cramps in the brachioscapular myotoma) or upper motor neuron (slowed movements, hyperreflexia, hypertonia and spasticity). The legs remain relatively preserved. Later on, bulbar involvement ensues causing dysphagia, drooling of saliva, dysphonia, tongue atrophy with fasciculations, spastic dysarthria ('hot potato speech') or aspiration. Signs of pseudobulbar palsy (bilateral corticobulbar involvement) usually evolve during the course of the disease and may become evident such as brisk jaw jerk, uncontrolled emotional incontinence with sparing of cognitive function. Autonomic functions and eye movements remain always preserved. An initially tentative diagnosis may become more secure as the disease progresses. Hence a triad of atrophic weakness of the hands and forearms, slight spasticity in the upper and lower limbs, and generalized hyperreflexia in the absence of sensory symptoms usually leaves little doubt. Upper MN and lower MN findings (clinically or on EMG) in at least three of four anatomical regions (bulbar, cervical, thoracic and lumbosacral) are required for definite clinical diagnosis. Forced vital capacity is used for follow-up of respiratory muscle strength. SNAPs should be normal. Plasma homocysteine levels may be increased in patients with shorter time to diagnosis. The NCVs are normal but the amplitude may be slightly reduced. CSF protein is normal or slightly elevated. Intriguingly, SEPs are abnormal. Brain MRI may show slight atrophy of the motor cortices and degeneration of the motor tracts (subtle symmetric increased T2 signal intensity in the posterior limb of the internal capsule, brainstem, and spinal cord).  Variants in the pattern of evolution exist (progressive bulbar palsy; early thoracic, abdominal, or posterior neck muscle involvement; hemiplegic forms; proximal limb or shoulder girdle amyotrophy etc.). 20% of familial forms and 5% of the sporadic forms have mutations in the gene for cytosolic, copper/zinc superoxide dismutase (SOD1) encoded on chromosome 21q22.1 and are transmitted as an autosomal dominant trait. Invariably, death from respiratory failure usually occurs within 3-5 years from onset of symptoms in 50% of patients.  5-year survival after diagnosis is about 7%. Familial ALS may present as an LMN syndrome. Riluzole (50mg bid), a glutamate antagonist, prolongs tracheotomy free survival by 36 months. Approximately 10% of patients stop the drug because of adverse events, principally gastrointestinal intolerance and asthenia. CBC and liver function tests should be monitored every month. Riluzole does not produce an improvement in symptoms. Physiotherapy remains the mainstay of treatment. Weight loss should be tackled by early institution of percutaneous endoscopic gastrostomy feeding or gastrostomy. Sialorrhea is generally managed with anticholinergic agents including atropine or amitriptyline taken orally, hyoscine (scopolamine) transdermally, glycopyrronium bromide subcutaneously, or via gastrostomy. Noninvasive positive pressure ventilation (> 4 hrs/day) prolongs survival, but is less well tolerated in severe bulbar impairment. Criteria for its use: PaCO2 > 45 mmHg, nocturnal oxygen desaturation for 5 min of < 88%, FVC < 50% of predicted, or a max inspiratory pressure of < 60 mmH20. Patients with BMI > 21 predicts long-term survival. The following disorders in order of appearance are most commonly misdiagnosed as ALS: multifocal motor neuropathy with conduction blocks (anti-GM1 antibodies), CIDP, MG, MS, sensorimotor neuropathy, syringomyelia, cervical spondylitic radiculomyelopathy (neuroimaging, pain in neck and shoulders, sensory changes), and IBM. In relation to progressive bulbar palsy, MG, polymyositis, muscular dystrophy and Kennedy disease (X-linked) needs to be considered. MND has been observed in association with certain systemic conditions such as monoclonal gammopathy, lymphoma, thyroid disorders, hyperparathyroidism, HTLV-1 or HIV infections, heavy metal toxicity or high titers of anti-GM1 ganglioside antibodies.


Progressive bulbar palsy (PBP): This form of MND refers to manifestations which initially and predominantly affect bulbar muscles, leading to spasticity of the tongue (slurring of speech), pharyngeal and laryngeal muscles with atrophy, fasciculations and weakness. Ocular muscle function remains invariably preserved. Similar to ALS, pseudobulbar palsy may develop. The condition is inevitably progressive and ends with respiratory failure after about 2-3 years of onset. About one quarter of all MND start with PBP.


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 (EPM2A gene), 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.


SCA-7: This autosomal dominant disorder typically presents with progressive ataxia, upper motor neuron signs (brisk reflexes), macular or retinal degeneration with visual loss, and slow saccades. They often start in childhood. SCA-7 is mapped to chromosome 3p14.1-p21.1. Early onset cases may present with dementia. This form is often misdiagnosed as MS. SCA-7 constitutes about 5% of ADCAs.


Spinal muscular atrophy type III (SMA-III) or Kugelberg-Welander syndrome: This form of SMA affects the predominantly proximal muscles of the lower limbs (including pelvic girdle) followed by shoulder girdle and upper arm muscles. Adult forms are rare and affect mainly men. The disorder is autosomal recessive or autosomal dominant, but other patterns of inheritance exist. Bulbar muscles are spared and no pyramidal signs occur. Fasciculations, EMG and muscle biopsy findings are all characteristic for neural atrophy and allow to differentiate from LGMD. The disease is linked to 5q11.2-13.3 gene locus. Life expectancy is normal and is slowly progressive.


Spinal muscular atrophy type IV (SMA-IV): This form of SMA is either of autosomal recessive or dominant inheritance and is characterized by proximal weakness affecting the legs more than the arms. Bulbar involvement is unusual. The onset occurs on average after the age 25 years. It is often mistaken for limb girdle dystrophy. Life expectancy is normal and patients can walk with aids until their 50s. The disease is linked to 5q11.2-13.3 gene locus.


Distal spinal muscular atrophy : The age of onset is variable but generally before the age of 20 years. Autosomal recessive and dominant forms exist. The disease presents with distal weakness affecting the lower limbs more than the upper limbs (e.g. peroneal muscular atrophy with flaccid foot drop). Unlike in HSMN, nerve conduction studies are normal. Distal muscular dystrophy affecting the legs should be considered as another potential differential diagnosis. However the latter is easily identified since gastrocnemius muscles are preferentially affected and serum CK levels are tenfold increased. Life expectancy is normal. The disease is linked to 8p21 gene locus.


Progressive muscular atrophy (PMA): PMA is thrice as common in men than women. Some chronic varieties are hereditary. In 50% of cases PMA takes the form of a symmetric wasting of intrinsic hand muscles, slowly progressing to the proximal parts of the arms. Fasciculations and cramps are present. Bulbar involvement is often mild and occurs late in the disease. The only difference with ALS is the absence or diminished tendon reflexes and no signs of corticospinal tract disease. 5-year survival rate is 72% in patients with onset after the age of 50. Patients may survive >15 years.  The main differential diagnoses are MMN (IgM paraproteinemia, anti-GM1 ganglioside, focal conduction block and sensory nerve abnormalities), Kennedy syndrome, late-onset SMA, and diabetic polyradiculopathy or polymyositis.


Acute paralytic poliomyelitis: The disease is virtually eradicated in worldwide. However, there are still cases of vaccine-related poliomyelitis following oral live attenuated poliovirus (Sabin) vaccine, particularly in immunocompromised patients. The infection by a poliovirus occurs throughout the year in the tropics. Only a few percent of those infected develop the paralytic forms of poliomyelitis. Fever, diarrhea, lower motor neuron weakness usually maximal in 3 5 days. Lumbar > cervical, spinal cord > brainstem. The paralysis is usually asymmetrical, predominantly involving the proximal muscles (lower limbs) with pain and tenderness with typical weakness, flaccidity and areflexia. The extent is variable from one muscle group to complete tetraparesis. Wasting starts within a week and fasciculations are prominent. Up to 15% of cases will develop respiratory muscle failure. CSF analysis reveals polymorphonuclear pleocytosis (100-200 cells) with normal or raised protein 200 mg/dL (between week 2-3 of paralysis). Stool viral cultures are usually positive for polio 1, 2, and 3 or echovirus 4 (in pre-paralytic phase and through first 10 days of paralysis). Serum diagnosis with >4-fold increase in antibody titer between acute and convalescent sera confirms the diagnosis. Coxsackie infections, AIP, tetanus, MG, diphtheria, tick-borne central European encephalitis and brainstem encephalitis may occasionally enter the differential diagnosis.  A syndrome of extremely slowly progressive weakness (postpolio weakness) affecting muscles previously affected by paralytic poliomyelitis 2 to 3 decades before. Increased synthesis of intrathecal poliovirus is detectable in 2/3 of patients.


Monomelic SMA: These benign SMAs or lower MND occur chiefly in Asia (India subcontinent and Far East) and account for about 12% of MND cases. They occur in young men (mean 20 years of age) and present with asymmetric distal wasting and weakness confined to a single upper or lower limb without involvement of cranial nerves, pyramidal tracts, sensory, cerebellar or extrapyramidal systems. Areflexia and fasciculations are found. The disease stabilizes or its evolution slows down after steady progression for up to 2 years. Any later progression affects more the proximal muscles. EMG/NCVs show a neurogenic pattern w/o conduction block. Syringomyelia, multifocal motor neuropathy and HSMN can enter the differential diagnosis.


GM2 gangliosidosis (hexosaminidase deficiency): Late-onset forms of GM2 gangliosidosis: Tay-Sachs disease (hexosaminidase A deficiency) and Sandhoff (hexosaminidase A and B deficiency) disease exist. Late-onset forms (age of > 60 years) of GM2 gangliosidosis occur particularly in Ashkenazi Jew descendants, but have been identified in other populations as well. Early and dominant sensory disturbances (axonal sensory polyneuropathy) such as mechanoallodynia are often the first symptoms. In addition, almost half of the patients present with psychiatric manifestations (psychosis), slowly progressive SMA with muscle weakness (often limb-girdle in distribution) and nocturnal cramps and other combinations of MND (fasciculations, spasticity and amyotrophy), progressive spinocerebellar ataxia and ophthalmoplegia. Other manifestations such as dementia, dystonia, and seizures are less common. In contrast to chronic (or adult) GM1 gangliosidosis, extrapyramidal features (dystonia, parkinsonism) are not a prominent feature and are explained by the fact that in chronic (or adult) GM2 gangliosidosis storage neurons are more widely distributed (thalamus, substantia nigra and other brainstem nuclei, and cerebellum). MRI may reveal severe cerebellar atrophy. The diagnosis is based on serum and leukocyte total hexosaminidase (Sandhoff disease) and hexosaminidase A (Tay-Sachs disease), which decreased in both conditions (2 to 4% of normal). Further confirmation can be received from rectal biopsy (ganglion cells). GM2 gangliosidosis is autosomal recessive and the HEXA gene is located on chromosome 15q23-24. All patients with recessive atypical ataxia or unusual motor neuron disorder should be screened for lysosomal storage disease, particularly if the parents are consanguineous. The disease may mimick progressive muscular dystrophy.


X-linked spinal bulbar muscular atrophy (SBMA) or Kennedy disease: The hallmark of SBMA is distal atrophy with prominent bulbar signs. Onset of the disease is variable from 2nd to 5th decade of life, although most commonly patients seek medical attention between the 4th and 5th decade of life. The initial manifestation of this slowly progressive lower MND of adult men is often cramping of limb muscles, particularly the legs followed by proximal shoulder and pelvic girdle weakness and atrophy. Later on dysarthria and dysphagia develop. Almost pathognomonic are facial fasciculations and persistence of grimace-evoked contractions of the lower facial muscles. Mild sensory neuropathy is almost universal. Additional features include tremor, a variable degree of glucose intolerance (25% of patients), subclinical sensory neuropathy and signs of partial androgen insensitivity (gynecomastia, testicular atrophy and reduced fertility). Eventually the most severe weakness is bulbar with severely wasted tongue. There are no signs of upper motor neuron involvement. Serum CK levels may be increased. The disorder is caused by a CAG nucleotide expansion within the androgen receptor gene (chromosome Xq21-22). Genetic testing for SBMA is highly sensitive and specific. The prognosis is much better than ALS and total lifespan is usually not affected. Heterozygous women are symptomatic, although exceptional mild manifestations may occur. The 10-year survival is around.


Hereditary spastic paraplegia (HSP): Although dominant autosomal trait is the most common one, recessive and X-linked inheritance exist. HSP-I is characterized by onset before the age of 35 years. Progressive, spastic weakness in the distal legs with mild or absent sensory or sphincter involvement is characteristic. HSP-II develops after the age of 35 years, weakness is prominent, and reduced vibration, sphincter dysfunction and gait abnormalities are common. Additional features may be found including ichthyosis, retinitis pigmentosa, optic atrophy, cortical, or cerebellar atrophy, extrapyramidal features, sensory neuropathy, distal muscle wasting, mild age-related cognitive impairment, dementia, or epilepsy. Central motor conduction is only minimally prolonged. Autosomal dominant HSP (or pure HSP) has most commonly been linked to chromosome 2p21-24 (spastin gene, SPG4), but other loci have been identified (14q, 15q, 8q, 12q and 19q). Patients survive several decades.


Konzo: Insufficient soaking of the cassava roots used to produce flour results in acute and permanent symmetric spastic paraparesis. Blood cyanide levels are increased at the onset of the disease.


Primary lateral sclerosis (PLS): The onset is after the age of 40 years (male to female ratio 3:1). Pyramidal syndrome with weakness usually starts insidiously in an ascending order affecting first the legs resulting in spastic paraparesis and bladder spasticity. Over the years, finger movements become slower, arms become spastic and, finally, pseudobulbar syndrome (a brisk jaw jerk, stiff slow tongue, and a characteristic spastic dysarthria in which patients are described as sounding as if they have a hot potato in their mouth) develops. There are no sensory symptoms or signs. Progression over 3 years without evidence of LMND is considered an important diagnostic criterion. The evolution is slow over mean 8.5 years (range 515 years) with relative preservation of muscle strength and prominent emotional lability, usually without cognitive impairment. Recessive PLS form exist which are due to inactivation mutation in alsin gene. This condition needs to be differentiated from all other disorders with restricted bilateral UMND; MS, spinal cord compression by spondylosis or meningioma, myelopathic form of ALD, tropical spastic paraparesis, HIV myelopathy and HSP.


SCA-8: This form of autosomal dominant spinocerebellar ataxia presenting with mild truncal and limb ataxia, scanning dysarthria, impaired smooth pursuit and horizontal nystagmus, spastic paraparesis and reduced vibration, and is mapped to 13q21. Slowly progressive wheelchair bound in the 4th and 5th decades.


Cerebrotendinous xanthomatosis: This a rare autosomal recessive disorder caused by mutation of the sterol 27-hydroxylase (CYP27) gene and resulting in defective bile acid synthesis. The adult form is almost invariably characterized by juvenile cataract (97%), progressive neurological dysfunction (spastic paraplegia (often very prominent) (81%), low intelligence (poor attention, memory impairment) (66%) and cerebellar ataxia (56%)), chronic intractable diarrhea (since childhood) (50%) and bilateral Achilles tendon xanthomas (41%). Less frequently, seizures, sensorimotor demyelinating peripheral neuropathy and premature cardiovascular disease may occur. Serum cholesterol levels are reduced and cholestanol levels are increased (normal 0.2 + 0.2 mg/dl). Brain MRI scan reveals consistently bilateral signal hyperintensities in the dentate nuclei on FLAIR. Proton MR spectroscopy appears to be a useful measure of disease outcome. Treatment chenodeoxycholic acid can reverse neurological syndrome.


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.


Homocystinuria (type III): This autosomal recessive is caused 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.


Post-irradiation lumbosacral radiculopathy