Hereditary forms 


Hereditary sensorimotor neuropathy (HSMN): This is the most common cause of  distal leg muscle wasting and weakness ("peroneal muscular atrophy" syndrome), usually accompanied by pes cavus. The age of onset is variable and asymptomatic, yet affected, elderly relatives may be identified. In HSMN males are commonly affected, whereas females are more often asymptomatic. Positive sensory symptoms (paresthesias) are unusual and should rather suspect acquired neuropathy. Associated features (spastic paraparesis, optic atrophy, retinitis pigmentosa, deafness and mental retardation) can occur. With the availability of genetic testing, noninvasive accurate diagnosis is now possible and omits the need for nerve biopsies.

HSMN - I (Charcot-Marie-Tooth disease type 1 or adult-onset demyelinating): The age of onset of this mostly autosomal dominant (autosomal recessive, and X-linked forms exist) inherited demyelinating neuropathy is in the 1st to 2nd decade of life. Its prevalence is estimated at 1/2,500. Clinically, distal leg muscle atrophy ("inverted champagne bottle"), lost ankle jerks and weakness, usually accompanied by pes cavus characterize the disorder. Some hand weakness, tremor and limb ataxia (HSMN with ataxia or Roussy-Lévy syndrome) may ultimately develop. All modalities of sensation may be impaired distally in the limbs and acrodystrophic changes secondary to sensory loss may develop. Scoliosis, pupil abnormalities, or extensor plantar responses occasionally occur. Diaphragmatic weakness may cause dyspnea or respiratory failure. Palpable nerve thickening (great auricular nerve) is found in 25% of patients. CSF is normal but raised protein (> 1g/l) can be found. Motor NCVs in the median nerve are substantially slowed (> 12m/s and < 38 m/s) and SNAPs are absent or reduced (normal in SMA). Nerve biopsy shows segmental demyelination with hypertrophic "onion bulb" changes. 70% of patients have reduplication of PMP22 gene (type 1A) on chromosome 17p11.2. Other mutations (on chromosome 1 (P0 gene) in CMT1B, chromosome X (connexin 32 gene) and chromosome 10 (ERG2 gene) exist. Progression is slow. Déjérine-Sottas disease is now known to be early and severe forms of CMT1. Neurophysiologically HSMN - I needs to be differentiated from CIDP, but usually the clinical picture allows distinguishing. In addition, neurophysiologic examination of the first-degree relatives and molecular genetic testing contributes to the diagnosis.

HSMN - II (Charcot-Marie-Tooth disease type 2 or adult onset axonal form): The age of onset of this mostly autosomal dominant (X-linked and autosomal recessive forms exist) inherited axonal neuropathy is in the 2nd to 3rd decade. Males are more commonly affected than females. Onset can however be delayed until old age. Distal leg muscle wasting and weakness, with absent ankle jerks. Hand weakness, tremor and ataxia of the arms, sensory loss, generalized areflexia or pes cavus are less common than in HSMN - I. There is no nerve hypertrophy. Median motor NCV is normal or only slightly prolonged (> 38m/s), while SNAP is absent or reduced in amplitude. CSF is normal. Nerve biopsy shows axonal loss. In contrast to CMT1, the CMT2 gene (CMT2A) is mapped to chromosome 1p36, however variants exist (e.g. 2B linked to 3q, 2C linked to 12q etc.). Progression is rare. Late-onset HSMN should be differentiated from chronic idiopathic axonal polyneuropathy in which sensory features and progression are characteristic. Atactic forms of HSMN type II can be distinguished from FA and vitamin E deficiency by their inheritance pattern.


Hereditary neuropathy with liability to pressure palsies (HNPP): This condition also known as tomaculous (sausage-like) neuropathy is autosomal dominant with high penetrance but variable expression. Typically the onset of symptoms is in the 2nd or 3rd decade of life and translates in a tendency to develop painless focal and recurrent demyelinating sensory and motor peripheral mononeuropathies due to unusual vulnerability to pressure or traction. Exposed nerves such as ulnar nerve, radial nerve and superficial peroneal nerve are especially vulnerable. Painless brachial plexus lesions may result from traction or prolonged abnormal postures. Recovery occurs over days, weeks or months, but permanent disability may develop after recurrent episodes. Typically, patients experience tingling of the fingertips when using scissors. NCVs show prolonged distal motor latencies or reduced SNAPs with conduction blocks and minor slowing of motor conduction velocities both in affected and asymptomatic gene mutation carriers. Almost 80% of patients have a deletion of PMP22 gene at chromosome 17p11.2. Nerve biopsy shows sausage-like pattern of the nerve (also found in familial brachial plexus neuropathy, Ehler-Danlos and paraproteinemic neuropathy).


Hereditary sensory and autonomic neuropathy type I (HSAN-I): The age of onset of this autosomal dominant inherited neuropathy is in the 2nd to 3rd decade. All modalities of sensation, particularly pain and temperature sensation, from the distal part of the limbs (particularly feet) are gradually lost. Spontaneous distal lancinating shouting pain in the legs may occur early in the disease. Foot ulcers, calluses and foot deformity develop. Distal leg muscle wasting and weakness, and absent ankle jerks develop later. SNAPs are absent or reduced and motor NCVs are normal. The condition is linked to chromosome 9q22 (SPTLC1 gene).


Friedreich ataxia (FA): This form of ataxia is the most common hereditary form (autosomal recessive with variable phenotype) with a frequency of 1/50,000 in the population. Essential diagnostic criteria include its onset before the age of 25 years and <5 years after onset the development of the following: progressive gait ataxia, early areflexia in lower limbs, vibration and joint position sensory deficits, extensor plantar responses, and motor nerve conduction velocity >40 m/s in upper limbs with small or absent SNAPs consistent with axonal sensory neuropathy. Other features are scoliosis, club feet, cardiomyopathy (>50%), diabetes or impaired glucose tolerance (10%) and dementia. Optic neuropathy and deafness occurs in less than 25% of cases. Life expectancy of FA is on average 35 years, death occurring from heart failure. The locus is mapped to chromosome 9q13-q21.1 (frataxin). Frataxin results in intramitochondrial iron accumulation, which explains why FA is now considered a mitochondrial disorder. Abnormal ECG and echocardiography are seen in approximately 60% of cases. CSF is normal. The condition most frequently confused with FA is HSMN I. This demyelinating form of HSMN, is essentially characterized by autosomal dominant inheritance with slow conduction velocities (always <40 m/s). Late-onset FA (after the age of 25 years) (LOFA) is characterized with a slower progression and lower incidence of skeletal deformity. Investigations should include brain MRI, serum vitamin E and B12 levels, and a-fetoprotein levels and DNA analysis to detect GAA trinucleotide expansion.


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.


Abetalipoproteinemia or Bassen-Kornzweig syndrome: Almost 50% of patients with abetalipoproteinemia present with neurological manifestations. Age of onset is usually in the 1st or 2nd decades of life. Loss of night vision and steatorrhea are frequently the earliest symptom and precede weakness of the limbs with areflexia and sensory ataxia, later followed by cerebellar ataxia. Steatorrhea causing vitamin (A, E and K) malabsorption results in progressive unremitting spinocerebellar ataxia with loss of proprioception and vibratory sensory loss (tabetic type of sensory ataxia), areflexia and weakness (vitamin E responsive peripheral neuropathy), INO with nystagmus of adducting eye and retinitis pigmentosa (in later stages). Gastrointestinal symptoms may be mild or subclinical. ESR is low. Fresh blood smear with acanthocytes with hypolipidemia (reduced serum total cholesterol, apoprotein B (necessary for chylomicron formation), absent β-lipoprotein and low or absent chylomicrons, LDL-cholesterol and VLDL (essential for vitamin E transport)), low levels of plasma prothrombin, very low vitamin E and low serum levels of other fat soluble vitamins (except vitamin D which has its own transport system) are diagnostic. Urinary mevalonic acid levels are increased. NCVs reveal axonal neuropathy. SSEPs, VEP and ERG are abnormal. Sural nerve biopsy shows diminished numbers of myelinated fibers. The disease is autosomal recessive and caused by deficiency of microsomal triglyceride-transport protein (MTP gene mapped to chromosome 4q22-24). PET scan shows reduced [18F]dopa uptake in both putamen and caudate nucleus in severe and prolonged vitamin E deficiency. By the 2nd or 3rd decades patients are often bedridden. The syndrome needs to be differentiated from FA.


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.


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.


Familial amyloid polyneuropathy (FAP): These neuropathies are inherited as autosomal dominant traits and subclassified as FAP-I to IV. The onset of the disease is usually in the 3rd or 6th decade (median 33 years). FAP type I, presents with polyneuropathy with sensory dissociation starting at the legs and progresses in an ascending fashion. The polyneuropathy is characterized by early development of burning pain, with predominant impairment of pain and temperature sensation on examination, and clinical evidence of autonomic dysfunction suggestive for predominantly small-fiber neuropathy. In 50% of cases of FAP-I, the first signs are severe weight loss and sensory neuropathy of the hands and feet followed within a few years by progressive autonomic neuropathy (pupillary reactions, diarrhea, obstipation, impotence and postural hypotension). In 30% dysautonomia precedes the sensory symptoms. Subsequently, motor neuropathy with areflexia appears, first in the legs (particularly ankle dorsiflexors) and progressing gradually to the arms (small hand muscles). Trophic ulcerations may occur. Systemic involvement results in myopathy, myelopathy, restrictive cardiomyopathy, eye involvement, and nephropathy. A family history of neuropathy accompanied by cardiac and renal involvement helps in the diagnosis. CSF protein is often raised. NCVs show axonal degeneration neuropathy. DNA analysis shows a mutation in one allele of the gene coding for transthyretin. The prognosis is bad with progresses to death in a few years (mean of about 10 years). In contrast, another transthyretin mutation-associated neuropathy, FAP type II, has a more benign course. FAP type II often presents late, with typical onset in the 5th decade. Carpal tunnel syndrome (25%) may be the only manifestation for 1st or 2nd decades. Later, these patients develop a generalized distal symmetric polyneuropathy with pain and paresthesias, and autonomic neuropathy complicated by intestinal malabsorption and blood pressure dysregulation. Vitreous opacities occur early in the disease course. There is typically no renal or ocular involvement in FAP type II, although a restrictive cardiomyopathy may develop. Apo A1-associated FAP (FAP type III) shares many features with FAP type I, but typically manifests early renal amyloidosis (renal insufficiency) and a high incidence of duodenal ulcers. Gelsolin-associated neuropathy FAP type IV typically starts in the 3rd or 4th decade with corneal lattice dystrophy, followed by insidious development of carpal tunnel syndrome and progressive cranial neuropathies in the 5th to 6th decades. The facial nerve is commonly involved, with a preponderance of upper facial fibers. Other cranial nerves involved include trigeminal, hypoglossal and vestibulocochlear nerves. The facial skin is thickened at first but with time it becomes lax. A mild sensory peripheral neuropathy and mild autonomic involvement may develop, although large-fiber loss appears to be more prominent than small-fiber loss. For all FAP, deep rectal, subcutaneous fat or sural nerve (less sensitive) biopsy are the first step in the diagnosis, followed by immunohistochemical identification on biopsy material. The sensitivity of GI biopsies is 85%. Survival is on average 15 years after the onset of the disease and death is often caused by renal failure or heart failure. Mutation in transthyretin gene on chromosome 18 is the most common one.


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.


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.


Hereditary spinocerebellar ataxia (SCA): 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-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.


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), but other loci have been identified (14q, 15q, 8q, 12q and 19q). Patients survive several decades. X-linked spastic paraplegia: The adult form of this disorder is generally presenting as a mild progressive multifocal axonal polyneuropathy. Heterozygous female carries can develop a polyneuropathy in the 4th decade and often associates with dementia in the 6th decade. MR spectroscopy reveals reduced N-acetyl aspartate in white and gray matter of the brain. PLP gene is located on chromosome Xq21-q22.


Gaucher disease: Three clinically distinct neurologic syndromes have been identified of this autosomal recessive lysosomal disorder characterized by β–glucocerebrosidase deficiency: type I (chronic non-neuronopathic), type II (acute neuronopathic), and type III (subacute or chronic neuronopathic). Adult forms have been reported in type I and III. Although non-neuronopathic, Gaucher type I may present with atypical PD in the 4th - 6th decade. The clinical course is usually severe with aggressive progression and is refractory to levodopa therapy. Gaucher type III (chronic neuronopathic form) is a chronic, slowly progressive neurologic disorder which may develop in early adult life. Stimulus-sensitive myoclonus, generalized seizures, horizontal supranuclear gaze palsies, and cerebellar ataxia are the main clinical features. Certain ethnic groups are at risk for this disorders; Gaucher type I is commonly found in Ashkenazi Jews (incidence of 1 in 2,500 births), while type III is more common in Northern Sweden (Norbotten). The diagnosis is based on the measurement of β-glucosidase activity in white blood cells. The clinical course is not predictable by measurement of residual β-glucosidase activity. The disorder is caused by a mutation in the gene on chromosome 1q21.


Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP): The age of onset may vary from the 1st to 3rd decades of life. This maternally inherited (mitochondrial) disorder presents with the following key features:  ataxia, weakness and axonal sensory neuropathy, mild mental retardation, retinitis pigmentosa and clonic-tonic seizures. A spectrum of neurologic findings may coexist such as migraine, dysarthria, dystonia and pyramidal syndrome. NARP has been associated with obstructive sleep apnea. Serum and CSF lactate and pyruvate levels may be normal or can be slightly increased. Blood citrulline level may be low and has been proposed as surrogate marker for this disorder. Muscle biopsy is normal. Brain MRI findings shows cerebral atrophy, cerebellar atrophy accompanied with dilation of fourth ventricle, and high intensity lesions bilateral in the lenticular nuclei (T2 images). The diagnosis is based on leukocyte mitochondrial DNA analysis which reveals a heteroplasmic point mutation (T8993G) in the ATPase 6 gene of mtDNA. The disorder needs to be differentiated from Refsum disease and Usher syndrome.


Metachromatic leucodystrophy (MLD): The late-onset form of this slow progressive autosomal recessive disorder has classically been described as presenting in its adult form with psychiatric manifestations; behavioral problems and slowly progressive dementia (frontal or subcortical in nature). But in fact two distinct geno-phenotypes are found: those patients presenting initially with motor disturbance (spasticity) and cerebellar dysfunction (arylsulphatase A mutation P426L homozygotes) and followed at later age by psychiatric manifestations, and those with schizophrenic-like behavioral abnormalities, social dysfunction, and mental decline, but scarce motor deficit (arylsulphatase A mutation I179S heterozygotes). At later age both clinical pictures merge or overlap. NCVs reveal substantially impaired motor nerve conduction (segmental demyelination) even in the absence of clinical features of polyneuropathy. CSF reveals raised protein levels. Some patients may develop abdominal symptoms related to sulphatide gallbladder stones. Brain MRI shows periventricular leukodystrophy (with frontal predilection) or can be normal. A convenient way to demonstrate MLD is the sulphatide excess in urinary sediment. The laboratory diagnostic tests show marked decrease or absence of arylsulphatase A activity in the urine and white blood cells or cultured skin fibroblasts. Sural biopsy reveals accumulation of metachromatic material. Important to know is that 1/50 to 1/100 of the normal population are homozygous for a common pseudodeficiency mutation in the arylsulphatase A gene (P426L, chromosome 22q). The work up for MLD deserves attention in any atypical MS-like syndrome or peripheral neuropathy of unknown origin. The course is prolonged and survival into 5th and 6th decade is possible.


X-linked adrenomyeloneuropathy (X-AMN): The adult form of this X-linked recessive peroxisomal disorder starts on average at the age of 28 years and is predominantly confined to the spinal cord (adrenomyeloneuropathy). Cerebral involvement is observed in half of the cases. X-AMN is often misdiagnosed as “familial MS”. Slowly progressive spastic paraparesis with sensory deficit (predominantly reduced vibratory sensation), bladder dysfunction and mild distal mixed axonal demyelinating polyneuropathy are common features. These clinical symptoms are often preceded or followed by behavioral disturbances or frontal dementia (mania, psychosis and cognitive impairment) and are often misdiagnosed as brain tumor. Both neuroleptic and anticholinergic medications may result in significant side effects with little resolution of the underlying psychiatric symptoms. Adrenal insufficiency (Addison syndrome) develops in 70% of the patients before, during or after the onset of the neurological syndrome, and does not correlate with the severity of the neurological disease. 20% of heterozygous female patients may develop a late middle age syndrome, which resembles adrenomyeloneuropathy (spastic paraparesis, loss of vibration, long tract signs and peripheral neuropathy), but are unlikely to develop adrenal dysfunction. Other phenotypes are pure adrenal insufficiency or simply asymptomatic carriers. The diagnosis is confirmed by the presence of increased levels of saturated VLCFA in plasma (15% false negative in female heterozygotes) and cultured skin fibroblasts or white blood cells. CSF reveals increased intrathecal IgG. NCVs in patients with X-AMN are often abnormal and suggest a mixture of axonal loss and multifocal demyelination. Although MRI can be normal in up to 50% of patients, high signal intensities in the periventricular parieto-occiptal white matter (often asymmetric and mimicking brain tumor) have been reported in cerebral forms. However in 15% the initial lesions may be frontal. MRI findings may often provide the first clue to the diagnosis. A decreased N-acetylaspartate/choline ratio is found on MR spectroscopy. BAEP reveals prolonged latencies of III-V. The defective ALDP gene encodes for ATP-binding cassette transporter involved in transport of VLCFA into peroxisomes and has been mapped to Xq28.


Krabbe leukodystrophy (KLD): Three adult forms of this slowly progressive autosomal recessive disorder have been reported: (1) familial spastic paraplegia or tetraplegia, (2) an asymmetric pyramidal syndrome and (3) an asymptomatic form. Later on features such as frontal dementia, seizures, cerebellar ataxia, optic atrophy and demyelinating sensorimotor peripheral polyneuropathy appear. Motor nerve conduction is substantially reduced (NCVs may however be normal). CSF protein levels may be normal. Brain MRI may be normal but most often reveals increased signal intensity on T2 in the spinal pyramidal tracts, bilateral in the white matter of the cerebrum and brainstem. Proton MR spectroscopy shows increased choline and myoinositol in affected white matter. The diagnosis is based on the presence of low lysosomal galactocerebrosidase activity (<5% of normal) in white blood cells or cultured dermal fibroblasts. Some healthy individuals may have low enzyme activity. The gene maps to 14q25-31.


Anderson-Fabry disease (AFD): This X-linked recessive disorder of glycosphingolipid metabolism is due to a deficiency of the lysosomal enzyme αlpha-galactosidase A with accumulation of neutral glycosphingolipids within the lysosomes of endothelial, perithelial, and smooth muscle cells of the myocardial and renal systems. The average age at onset is highly variable, but the diagnosis is usually made around the age of 20 years. A majority of homozygous men develop severe multisystemic disease (classic form), characterized by cutaneous angiokeratomas, renal failure (30%), progressive neurological (sensorineural deafness (78%), burning neuropathic pain (acroparesthesias) and paresthesias distally in the limbs provoked by exercise or heat (77%), cerebrovascular complications (24%)) and cardiac involvement (dysrhythmias and structural abnormalities apparent on echocardiography). The average age at onset of cerebrovascular symptoms is around 30 years for hemizygous individuals and 40 years of heterozygous. The most frequent symptoms and signs are, in descending order of frequency: hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, headache, hemiataxia, and ataxia of gait, in the hemizygous group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms, in the heterozygous group. Elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and pathologic features. The NCVs show significantly decreased amplitudes of motor and sensory NCVs. For the hemizygous, the recurrence rate for cerebrovascular disease is 76% and the death rate 55%; 86% of the heterozygotes have recurrent cerebrovascular event(s) and 40% die. The cerebrovascular manifestations of AFB, in both hemizygous and heterozygous, are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur, and have a poor prognosis. Nevertheless, some affected men retain sufficient enzyme activity and remain asymptomatic for a long time; their main manifestation is hypertrophic cardiomyopathy. Female heterozygous carriers are usually asymptomatic; 15% of them, however, have severe involvement of one or several organs. Laboratory, histologic and molecular diagnosis identifies 100% of hemizygous and over 80% of heterozygous subjects. The median cumulative survival was 50 years. Biochemical diagnosis is based on a decreased level of plasma, tears, leucocyte or cultured fibroblasts α-galactosidase A activity. In addition, skin biopsy with ultrastructural examination of small blood vessels may be diagnostic. The gene is mapped to chromosome Xq22.


Tangier disease: This familial autosomal recessive disorder is characterized by the absence of HDL cholesterol. Most patients develop either relapsing/remitting multiple mononeuropathies or slowly progressive symmetrical sensory peripheral neuropathy resembling syringomyelia. NCVs are slowed.


Familial hypobetalipoproteinemia: Homozygous patients are clinically indistinguishable from patients with abetalipoproteinemia. They generally have low levels of apoprotein B, betalipoproteins, total cholesterol and LDL-cholesterol, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Heterozygous patients are usually asymptomatic are have part of the syndrome. The disorder is autosomal dominant and is caused by mutations in the apoprotein B gene (chromosome 2p24).


Hereditary porphyria: The porphyrias that mainly cause neurologic features are acute intermittent porphyria (AIP), hereditary coproporphyria, variegate porphyria and d-aminolevulinic aciduria. Although these are distinct disorders, they all present in a similar way: abdominal or back pain (89%) followed by neurologic (33%), psychiatric (28%) and cardiovascular (25%) symptoms. Only hereditary coproporphyria and variegate porphyria present with photosensitive skin lesions. Limb, neck and chest pain and muscle weakness occurs commonly in patients with an acute attack of AIP. During an acute attack (often provoked by drugs, hormonal changes, infections, reduced dietary carbohydrate intake), these motor symptoms can occur with other neurologic abnormalities, including autonomic dysfunction, seizures and behavioral changes (encephalopathy). Neuropathy (acute symmetric proximal weakness or distal ascending or descending weakness followed by truncal sensory loss) occurs in 40% of acute attacks, usually 1-4 weeks after onset and can mimic Guillain-Barré syndrome. Typically, the ankle jerks are often preserved despite absent knee jerks. Cranial nerves can be affected particularly ocular, VII and X. Autonomic dysfunction in form of tachycardia, hypertension, and urinary retention are common. NCVs are consistent with axonal neuropathy. Very often patients are labeled as hysterical and have a drug-seeking behavior. Provoking factors may be surgical intervention. Marked elevation of urinary levels of porphobilinogen (urinary porphobilinogen (normal 0-4 mg/24 hr) and increased total porphyrins (0-300 nmol/24 hr), decreased erythrocytic porphobilinogen deaminase (deficiency) and increased erythrocytic protoporphyrin) is a hallmark of all acute porphyrias except d-aminolevulinic aciduria (normal delta-aminolevulinic acid (0-7 mg/24 hr)). Typing of the porphyria requires quantitative assay of porphobilinogen, except d-aminolevulinic acid and porphyrins in urine and feces. AIP is an autosomal dominant disorder resulting from a mutation in the porphobilinogen deaminase gene (chromosome 11). Treatment should focus on avoiding drugs which induce cytochrome P 450 system. Glucose infusion decreases ALA synthetase activity.


Refsum disease: Onset is usually in the 2nd or 3rd decade. The course of the disease may be subacute, progressive or relapsing. The tetrad of Refsum disease consists of delayed retinitis pigmentosa (may precede the biochemical abnormalities by years), cerebellar ataxia, distal demyelinating predominantly motor polyneuropathy and elevated CSF proteins without pleocytosis (albuminocytologic dissociation). In addition, progressive deafness, diabetes and heart failure resulting from cardiomyopathy are present in most cases. Other clinical features, less commonly found are cataract, ichtyosis, anosmia, diffuse skeletal hyperostosis, liver and kidney disease. Night blindness is the first symptom followed by progressive demyelinating symmetric distal neuropathy (affecting predominantly vibration and proprioception and the legs more than the arms) and ataxia. Peripheral nerves may be hypertrophic. In contrast with the degree of retinitis pigmentosa, the neuropathic findings and cardiac involvement correlates very well with the plasma phytanic acid levels. Plasma phytanic acid is increased (normally < 0.2 mg/dl), but normal phytanemia has been reported. In the latter the issue needs to be resolved by determination of the activity of phytanic acid oxidase in skin fibroblasts. Sensory and motor NCVs are very low < 10 m/s. MRI may show cerebellar atrophy. The disorder is autosomal recessive and caused by mutation in the phytanoyl-CoA hydroxylase gene (chromosome 10pter-p11.2). Heterozygous carriers do exist and can be identified by the activity of phytanic acid oxidase in cultured fibroblasts. Cardiac failure may be the cause of sudden death.


Symmetrical benign lipomatosis or Madelung disease: This autosomal dominant, mitochondrial or sporadic disorder is characterized by the development of an axonal sensorimotor neuropathy with occasional autonomic features. The disease is most common in middle aged men with a history of alcohol abuse. Patients present with multiple symmetric lipomata over upper trunk and proximal arms, presenting like a bull-neck or simple obesity.


Kanzaki disease: This autosomal recessive lysosomal disorder is due to a deficiency α-N-acetylgalactosaminidase. The average age at onset is highly variable, and is characterized by cutaneous angiokeratomas, mental decline, progressive sensorineural deafness with vertigo and sensorimotor demyelinating polyneuropathy. The average age at onset of cerebrovascular symptoms is around 30 years for hemizygous individuals and 40 years of heterozygous. Brain MRI shows periventricular (posterior) WMHI and atrophy.  Biochemical diagnosis is based on a decreased level of α-N-acetylgalactosaminidase in plasma and cultured fibroblasts.



Non-Hereditary forms 


Drugs-induced polyneuropathy: The list of drugs causing polyneuropathy is exhaustive. Some of the most commonly used once will be described.


Ethambutol - optic neuropathy and sensory neuropathy

Isoniazid - slow acetylators may develop peripheral polyneuropathy with paresthesia and numbness as initial manifestations. Hyperalgesia and muscle cramps can occur. Vitamin B6 should be administered to treat or prevent this polyneuropathy.

Vincristine - Paresthesias, areflexia and mild autonomic symptoms are the initial symptoms. Autonomic features can be quite severe (paralytic ileus, acute abdomen, impotence or postural hypotension). Symptoms of polyneuropathy should prompt dose reduction. Permanent absent ankle jerks is commonly noted in asymptomatic patients.

Other drugs include; alpha-interferon, amitriptyline, colchicine, chloroquine, cimetidine, dapsone, didanosine, disulfiram, hydralazine, lithium, metronidazole, nitrofurantoin, phenytoin, pyridoxine, paclitaxol, tryptophan, nitrous oxide.


Amiodarone - symmetric distal sensorimotor demyelinating polyneuropathy months after starting treatment (6% of patients). Severe weakness can be seen and CSF protein is raised.

Cisplatin - symmetric distal sensory demyelinating polyneuropathy weeks after starting treatment (almost 100% of patients). Sensory NCVs are abnormal while motor conduction is normal. Severe weakness can be seen and CSF protein is raised. Partial or complete recovery may occur after cessation of cisplatin, but can take more than one year.

Other drugs include chloroquine, suramin and  gold.

Neuronopathy: thalidomide, pyridoxine, cisplatin.


Toxic polyneuropathy

Acrylamide polyneuropathy: High-dose intoxication which occurs after drinking of contaminated water causes subacute encephalopathy followed some days later by mild polyneuropathy. Chronic low dose intoxication (construction workers) results in polyneuropathy within 4 weeks after exposure. Diffuse areflexia is an early sign. Ataxia may be prominent. The neuropathy involves both sensory and motor. Contact dermatitis, blistering and hyperhydrosis of the palms and the soles may occur. SNAPs are small or absent. Sural nerve biopsy shows degeneration and regeneration of axons.  Complete recovery is possible.

Acute arsenic neuropathy: This type of poisoning occurs either acute or chronic (smelting workers). In acute poisoning neurologic symptoms appear 2-3 weeks after the initial gastrointestinal manifestations (abdominal burning pain, nausea, vomiting and diarrhea within hours-days of ingestion) or shock. Subacute polyneuropathy (7-14 days) presenting as numbness and often painful paresthesias with loss of vibration and position sense are the initial manifestations, subsequently followed by leg muscle weakness. Ankle jerks are invariably lost. SNAPs are absent and motor conduction is initially mildly slowed. Sural nerve biopsy shows axonal degeneration. Improvement over years occurs but is often incomplete. Other features in acute poisoning are encephalopathy, pancytopenia, eosinophilia, liver and/or kidney failure depending on the amount.  Chronic arsenic exposure in industrial workers may produce an asymptomatic sensorimotor neuropathy detectable only by NCVs. Mees lines and sole hyperkeratosis develop. CBC reveals anemia with basophilic stippling.

Thallium polyneuropathy: High doses of thallium (rodenticide) cause shock due to gastroenteritis and dehydration. When this initial phase is survived sensorimotor neuropathy becomes apparent in a few days. Sensory symptoms occur first and consist of painful paresthesias and allodynia affecting the feet. The reflexes remain preserved. The neuropathy progresses rapidly to involve the respiratory and bulbar muscles resembling GBS. Associated autonomic neuropathy results in tachycardia and hypotension. CNS manifestations are optic neuropathy, ataxia, confusional psychosis and involuntary movements.  Systemic features include dark pigmentation at the hair followed by rapid complete alopecia, dry skin, Mees lines on the nails helps to differentiate this form of neuropathy from other forms of acute polyneuropathy. Sural nerve biopsy shows axonal degeneration.

Lead polyneuropathy: Workers in metal smelting and battery (fumes) manufacturing are often the subject of chronic inorganic poisoning. The presentation is very similar to porphyria. Abdominal cramps are often the first manifestation. Classically a pure motor neuropathy develops affecting most often the radial or peroneal nerves. Sensory loss is uncommon. Anemia, basophilic stippling of red cell precursors and free erythrocyte protoporphyrin level are the best guide to chronic lead exposure. Motor NCVs may be slowed. Sural nerve biopsy shows loss of the large myelinated axons.

Mercury polyneuropathy: Chronic exposure to inorganic or elemental mercury produces mild sensorimotor peripheral polyneuropathy. Elemental mercury poisoning resembles MND. Organic mercury poisoning (e.g. Minamata disease) typically causes the combination of paresthesias, sensory ataxia, and visual field constriction. Paresthesias around the mouth and fingers and toes with sometimes normal NCVs may point towards the diagnosis. Measurement of mercury levels in blood, urine and hair confirm the diagnosis.

Other compounds:

Carbon disulphide: In rubber vulcanization, distal sensorimotor loss and areflexia affecting the legs.

Ethylene dioxide

Herbicide: early manifestations are nausea, vomiting and diarrhea followed by a few days by painful paresthesias in the fingers and toes. Motor NCVs are slowed.

Hexacarbons: Solvents in glue may cause sensorimotor neuropathy starting in the fingers and may develop into severe symmetric distal sensory and motor loss. Severe weakness may be mistaken for GBS. NCVs are slowed.

Pesticide: Peripheral polyneuropathy develops a few days or weeks after exposure to the pesticide. In organophosphorus poisoning predominantly motor neuropathy have been reported 1-3 weeks after exposure. The initial manifestation consist of cramping in distal leg muscles accompanied by distal paresthesias and numbness Progressive distal leg muscle weakness and hyporeflexia develop, followed by similar weakness of the arms. Demonstrable sensory signs are mild or absent. Superimposed pyramidal signs may be found. NCVs show denervation  with little or no slowing of NCVs.


Chronic ischemic monomelic neuropathy (CIMN): With severe ischemia, most patients experience activity-induced pain and trophic skin changes including ulcerations. Rest pain in toes or foot, numbness, burning and paresthesias in the ischemic foot due to peripheral nerve ischemia are the most common symptoms. Hyperalgesia, toe weakness, hyperesthesia, and pallanesthesia in the distal leg are present in over 50% of patients and are usually asymmetric. NCV reveals predominantly sensory neuropathy with reduced or absent sural SNAPs (often bilateral). Tibial motor amplitudes are reduced, while distal latencies, conduction velocities, and vibration thresholds are usually similar in both legs. The creation of AV fistula in the arm for hemodialysis can cause a distal axonal neuropathy due to vascular steal syndrome.


Neuralgic amyotrophy: The hereditary form of neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder characterized by recurrent attacks (with sometimes decades in between) of pain, sensory disturbances, weakness, and muscle atrophy in brachial plexus distribution. These attacks are typically followed by a period of recovery, often incomplete, requiring weeks or months. Residual deficits may accumulate. Strenuous exercise, pregnancy, and the puerperium may trigger attacks. Distinctive associated dysmorphic features are hypotelorism, unusual skin folds and ring-shaped skin creases (around the neck in adults, in babies “Michelin tire babies”) cleft palate, cutis vertices gyrata (streaked scalp lines) and epicanthal folds. NCVs reveal axonal damage with normal or slightly reduced NCVs. The hereditary form needs to be differentiated from the idiopathic forms (Parsonage-Turner syndrome) and symptomatic forms caused by B. burgerdorfi (Lyme disease). The locus for hereditary brachial neuralgic amyotrophy is mapped to chromosome 17q25.


Chronic idiopathic axonal polyneuropathy (CIAP): The onset of CIAP is in the 6th decade of life with mild sensorimotor neuropathy worse in the lower limbs. All modalities of sensation are impaired but paresthesias are rarely present. NCV studies indicate axonal degeneration. Progression is slow. Differential diagnosis include neuropathies with paraproteinemia, HSMN type II, lumbar canal stenosis and vasculitis.



Neuropathy associated with paraproteinemia


Neuropathy associated with benign monoclonal gammopathy of undetermined significance (MGUS): This benign condition is found in 10% of patients with idiopathic often painful sensory peripheral polyneuropathy and usually occurs between 3rd - 8th decades. Paraproteinemia (serum levels by immunoelectrophoresis of IgG <3,000 mg/dl, routine serum protein electrophoresis fails to detect these paraproteinemias) and lymphadenopathy are found in MGUS. A variety of neuropathies including mononeuritis multiplex, predominantly demyelinating type are found. Amyloid neuropathy and vasculitic neuropathy associated with cryoglobulinemia containing monoclonal RF. In general, the antibody tests do not have a prognostic value in terms of neurologic deficit or outcome.

CIDP-like polyneuropathy (CIDP-MGUS) - demyelinating polyneuropathy indistinguishable from CIDP are usually associated with IgG and IgA paraproteinemia. They have a slow progression, cause less severe disability and have prominent sensory symptoms than their idiopathic counterpart. The CIDP found in Waldenström macroglobulinemia may antedate the systemic illness by a few years.

IgM monoclonal gammopathy demyelinating polyneuropathy – IgM monoclonal gammopathy is the commonest form of the subgroup of patients with polyneuropathy. The onset is late and predominantly male are affected. The neuropathy is always symmetric and begins distal in the lower limbs with numbness, paresthesias and imbalance and occasionally weakness. Sensory signs usually develop before motor signs. Mostly patients have a chronic and slowly progressive, distal acquired sensory dominant demyelinating polyneuropathy. All patients will ultimately develop upper limb postural tremor and ataxia. ESR is usually normal. 50 - 60% of patients will have anti-MAG antibodies. The diagnosis can be made by sural nerve biopsy (chronic segmental demyelination, often with axonal degeneration). Anti-MAG antibodies help to confirm the favorable prognosis of the neuropathy. The disorder stabilizes after 2 - 5 years. Response to immunomodulator therapy is generally favorable.

Polyneuropathy associated with monoclonal gammopathy and anti-ganglioside antibodies - 15% of patients with polyneuropathy associated with monoclonal gammopathy have antiganglioside antibodies  (GA1, GM1, GM2, GD1a, GD1b or GQ1b) particularly those with demyelinating polyneuropathy and IgM monoclonal gammopathy. Anti-myelin-associated glycoprotein antibodies are increased in 30% of patients. Several types have been described: (1) MMN pure motor neuropathy often multifocal with conduction block, anti-GM1 and GD1b antibodies; (2) predominantly sensory polyneuropathy due to combined axonal degeneration and demyelination associated with antisulfatide antibodies; (3) chronic ataxic neuropathies associated with anti-GQ1b or GD1b antibodies and intermittent ophthalmoplegia are found in IgM paraproteinemia and CANOMAD syndrome. Multifocal motor neuropathy with conduction block (MMN): This chronic idiopathic neuropathy may occur at any age and presents usually as a slowly progressive asymmetrical distal limb weakness with minimal or no sensory impairment later on followed by muscle atrophy (may be accompanied by fasciculations, cramps and myokymia). The disease usually begins and remains more prominent in the upper extremities. The first symptom is often inability to extend a single finger. The most striking clinical feature is the multifocal distribution of the weakness, which, in the beginning, may be localized within the territory of individual peripheral nerves. Fasciculations are rare and cranial nerve involvement with bulbar palsy can occur. Reflex loss is usually restricted to the affected areas. Sensation is essentially normal. CSF is normal. NCVs show a combination of multifocal motor conduction block, prolonged or absent F- waves, prolonged distal latencies, reduced motor NCVs, or motor axonal loss with EMG evidence of denervation. Motor conduction block occurs most frequently in the ulnar and median nerves, both proximally and distally. But conduction block may be seen at any level of the peripheral nerve including the root, plexus, compression points (elbow for ulnar nerve, tibial head for peroneal nerve, etc.), or along a random segment. If parts of the nerve are not accessible for NCVs, significant weakness in non-wasted muscles can substitute for it. A unique electrophysiologic feature of MMN is that sensory NCVs are typically normal, even across a segment of motor conduction block. The EMG in MMN typically shows evidence of axonal degeneration with fibrillation potentials and positive sharp waves in atrophic muscles. Sural nerve biopsies are either normal or show evidence of perivascular inflammation, demyelination, or reduced myelinated fiber density. The diagnostic feature remains the demonstration of conduction block restricted to the motor fibers of a nerve, normal SNAPs, and the presence of serum anti-GM1 IgM polyclonal antibodies found in at least 1/3 of patients. Deterioration is steady or stepwise over years. The major differential diagnosis is CIDP, PMA and ALS. Early in the disease course weakness is more pronounced than atrophy in affected muscles. This is an important clinical feature distinguishing MMN from MND, in which atrophy is generally consistent with the degree of weakness. Note that motor conduction block also occurs in compressive neuropathies, GBS, and CIDP. Human IV immunoglobulin (0.4 grams/kg/day for 5 consecutive days) is the treatment of choice. The onset of improvement occurs within 14 days, and the effects last approximately 2 months. Patients, therefore require frequent boosters to maintain their functional gains. Clinical improvement is not associated with a consistent decrease of anti-GM1 antibody titers and is not invariably accompanied by a reduction of motor conduction blocks. In contrast to CIDP, prednisolone and plasma exchange are ineffective or, particularly steroids may dramatically worsen the neurological condition.  Multifocal motor axonopathy (MMA) can present with asymmetric weakness and axonal electrophysiological features. It needs to be differentiated from LMN syndromes in particular adult progressive SMA. EMG and CSF help to distinguish MMN from CIDP and multifocal acquired demyelinating motor and sensory neuropathy. IV immunoglobulin improve conduction block. Pregnancy may worsen MMN.


Neuropathy associated with paraproteinemia and anti-chondroitin sulphate antibodies: This consists mainly of sensory axonal degeneration neuropathy occasionally found in patients with IgM-κ or -λ paraproteinemia. The first symptoms are usually peripheral numbness, paresthesias or pain. All sensory modalities may be affected. In some patients the disease is associated with epidermolysis.


Neuropathy associated with polyclonal gammopathy: Angioimmunoblastic lymphadenopathy with dysproteinemia is often manifested by widespread lymphadenopathy. Most patients have rapid course and systemic manifestations including weight loss, high fevers, hepatomegaly, lymphadenopathy and anemia, and dysproteinemia typically polyclonal immunoglobulin. Neuropathy are rare and can present as mononeuritis multiplex. Castleman disease may be associated with lymphadenopathy and plasma-cell dyscrasia. Fever, nocturnal sweating, weight loss, malaise, organomegaly, lymphadenopathy, edema, pleural and pericardial effusion or ascites, rash are typical findings. Anemia and hypoalbuminemia and highly elevated ESR (>60 mm/h) are present. Occasional monoclonal gammopathy (often λ chain) are detected and in those conditions overlaps with POEMS syndrome. The neuropathy presents as distal and symmetric with predominantly sensory features, weakness developing in later stages. The NCVs indicate predominantly demyelinating polyneuropathy.


Neuropathy associated with malignant monoclonal gammopathy: These include multiple or osteosclerotic myeloma, lymphoma, Waldenström macroglobulinemia and POEMS.

Myelomatous neuropathy: Serum levels of IgG monoclonal gammopathy >3,000 mg/dl indicate malignant plasma-cell dyscrasia most commonly multiple myeloma, whereas lower levels indicate MGUS. 40% of patients with osteolytic multiple myeloma have neurophysiologic evidence of neuropathy, however only 5% develop symptoms. A wide range of neuropathies can be found: chronic demyelinating sensorimotor and small-fiber amyloid peripheral neuropathy (mainly affecting pain and temperature perception) and paraneoplastic sensory neuropathy (affecting distal parts of the arms and legs).

Polyneuropathy, organomegaly, edema, M band, skin changes (POEMS syndrome): Average onset at 50 years. At least three of the features summarized in the acronym need to be present for the diagnosis. Predominantly distal sensorimotor demyelinating neuropathy affecting the four limbs may occur in association with a specific syndrome: papilledema, gynecomastia, impotence, glucose intolerance, edema, hepatosplenomegaly, skin changes (thickening of the skin of the hands, brownish discoloration of the skin (hyperpigmentation), clubbing, sclerodermatoform changes at elbows, hands and mouth) and paraproteinemia with IgA-λ. Either osteosclerotic myeloma, or Castleman disease may underlie this clinical syndrome. POEMS is associated with hematological tumors (myeloma, Castleman disease, extramedullary myeloma). In fact 2/3 of patients with POEMS syndrome have the plasma-cell variant of Castleman disease. Serum level of vascular endothelial growth factor (VEGF) may be elevated particularly in case of necrotizing vasculitis. The neuropathy presents as distal and symmetric sensorimotor neuropathy affecting touch and vibration predominantly, weakness is initially distal but progressing to proximal muscles. The NCVs reveals axonal loss and demyelination w/o conduction blocks. Serum M-protein (usually IgA or IgG). ESR is generally normal. CSF shows high protein no cells. The disorder is progressively disabling, but after therapy recovery is observed in 50% of patients, still there is 50% mortality rate).

Peripheral neuropathy associated with lymphoma: Five types have been identified; GBS, CIDP (relapsing form), sensory neuronopathy, subacute motor neuropathy and asymmetric polyneuropathy. Asymmetric progressive painful sensorimotor neuropathy is a typical finding in intravascular lymphomatosis. Over 50% of patients have systemic lymphoma at the onset of the neuropathy and CSF contains tumor cells.


Chronic ataxic neuropathy with ophthalmoplegia, M-proteins, cold agglutinins and anti-disialated ganglioside antibodies (CANOMAD): The onset is in adulthood and is often preceded by fixed or relapsing/remitting uni-or bilateral ocular and bulbar palsies (usually abduction) weeks before the polyneuropathy ensues. The latter is a highly characteristic chronic usually asymmetric sensory ataxic and affects the arms much more than the legs (preserved motor function in the limbs). Dysphagia is present and Rombergism and pseudoathetosis are observed. NCVs and nerve biopsy reveal demyelinating and axonal features. Anti-GD1b or GQ1b (consistently present) antibodies, IgM paraproteins and cold agglutinins are present. Initially the syndrome is present only partially. There is partial response to IV immunoglobulin.


Paraneoplastic sensory neuronopathy: Women are more commonly affected than men. The neuronopathy precedes the tumor symptoms by 6 months - 3 years and develops subacutely over weeks and then stabilizes. Peripheral neuropathy is the presenting symptom in 95% of patients, while CNS and autonomic neuropathy present in 40% and 30% of patients, respectively. The course of the neuropathy is usually subacute (55%) or progressive (40%). Clinically, the neuropathy is mostly sensory (sensory ataxia) (70%) or sensorimotor (25%). At onset, symptoms are symmetrical (65%), asymmetrical (25%) or multifocal (10%) with pain (uncomfortable paresthesias) as a predominant manifestation (80%). The arms are most commonly affected often in an asymmetric way. Impairment of all sensory modalities, gait ataxia and areflexia are common. Amyotrophy and fasciculations are rare and strength is normal. Occasionally they coexist with limbic encephalitis (encephalomyeloneuritis). Electrophysiology showed the axonal/neuronal pattern to be the most frequent (50% of studied nerves) with reduced or absent SNAPs and normal CMAP. In patients with sensory neuropathy, 88.5% of sensory nerves are abnormal, mostly with an axonal/neuronal pattern. In addition, 47% of motor nerves are abnormal. Needle EMG/NCV studies showes only limited evidence of motor neuron degeneration in both sensory and sensorimotor neuropathy. The CSF is usually lymphocytic with raised protein. Serum and CSF may contain high titers anti-Hu (ANNA-1) antibodies.


Paraneoplastic sensorimotor neuropathy: They may precede or follow the tumor symptoms with mild forms found in 25% of patients with lung cancer. The onset is mostly subacute with limb weakness, sensory disturbance, and areflexia. NCVs reveal axonal degeneration. Typical GBS or CIDP (relapsing form) may be found.


Paraneoplastic vasculitic neuropathy: Mononeuritis multiplex presenting like a painful asymmetric neuropathy occurs with lymphoma and prostate or lung cancers. The symptoms may precede the tumor symptoms. Biopsy shows microvasculitis.


Leprous neuropathy: Leprosy (acid fast, intracellular gram-positive M. leprae) is the most common cause of neuropathy. Suspicion of leprosy should be raised in residence in or immigration from a high-risk geographic area (e.g. India and Africa). The combination of skin lesions and chronic sensory neuropathy or painful mononeuritis multiplex are the hallmark of leprosy. In tuberculoid forms (occurs in patients with relatively intact cell-mediated immune system), dermal nerve involvement is rapid, and presents as sharply delineated, anesthetic erythematous plaques, or hypopigmented macules, associated with motor or sensory loss (light touch, temperature, and pain) in the distribution of one or more damaged peripheral nerves. Virtually all skin lesions lose the ability to sweat. In addition, there is hair loss in distal lower extremities and poorly healed skin lesions on thigh, calf, or fingers resulting from previous burns and injuries. Particularly, the cold skin areas are affected (the pinnae of the ear, distal extremities, and the tip of the nose). Superficial nerves, particularly the ulnar, superficial radial, median nerves, greater auricular and superficial peroneal nerves, can become thickened and firm, and if the neuritis is active, it may be tender or painful. Skin and nerve biopsies show granuloma but very few bacilli. In lepromatous leprosy, there is extensive skin involvement with erythematous macules, papules, or nodes. This form occurs in patients with no immune response to the bacteria. Leonine face with thickening of the ear lobes and nose. Progressive symmetric polyneuropathy with preserved tendon reflexes and preserved sensation or even hypersensitivity of the plantar surfaces of the feet are typical findings. Dimorphous forms of leprosy (unstable immune response to the organism) is a form with features of previous described forms.  In advanced stages, profound pain and temperature loss, with trophic ulcers and autoamputations can be seen. The diagnosis can be confirmed by skin biopsies or smears from both center and edge of a lesion, and demonstrate acid-fast bacilli by Ziehl staining. Nerve biopsy (medial branch of the radial cutaneous nerve and the sural nerve) is useful in cases without skin lesions. Lepromin skin test (response to the intradermal injection of 0.1 ml of standard suspension of killed M. leprae) is positive in tuberculoid forms only. If the disease is suspected the therapy should not be postponed. The therapy will not allow recovery of nerves already affected. Lepromatous leprosy therapy should continue for at least 2 years until all biopsies are negative. In the tuberculoid type blood analysis may show mild increased ESR (10-15 mm/h) with mild increased WBC particularly neutrophils. The Lepromin test shows a biphasic response which occurs first at 24-48 hrs and a second at 4 weeks. It does not confirm the diagnosis of active disease, yet is useful in classifying the form of the disease. For multibacillary leprosy (lepromatous and borderline cases), treatment includes rifampicin, clofazimine, and dapsone. Treatment should be given for a minimum of two years, and preferably until the patient's skin smear is negative (especially in patients with skin smear bacterial index > 4.0). For paucibacillary (borderline and indeterminate cases), treatment with both rifampicin and dapsone is recommended. Treatment for the neuritis and nerve function impairment includes corticosteroids which are used to prevent further damage and facilitate recovery. Therapy is most effective in recovery of nerve damage of less than 6 months, and recovery usually occurs within the first 3-4 months. Steroid treatment is given for about 6 months, with a slow taper over several months to a maintenance dose.


Wernicke encephalopathy: The triad of acute confusion, ataxia and ophthalmoplegia is typical for Wernicke syndrome. Beriberi polyneuropathy is often found and consists, in contrast to alcoholic polyneuropathy, of non-painful motor neuropathy affecting distal leg muscles. Painless nutritional optic neuropathy or "nutritional amblyopic or tobacco-alcohol amblyopia" may occur. Initially, blurring or fogging is noticed at the point of fixation, followed by a progressive decline in visual acuity, which may be rapid. Visual field defects are nearly always central or cecocentral. The diagnosis of Wernicke encephalopathy is very suggestive after glucose load in chronic malnourished alcoholics but also occurs in other thiamine deficiency states (parenteral malnutrition, hyperemesis, impaired gastrointestinal function). Thiamine status can be evaluated by measuring total thiamine concentration in whole blood (>20 ng/ml) and erythrocyte transketolase activity (>124 U/L). Abnormal T2 and FLAIR sequences on MRI in mamillary bodies, periaquaductal gray matter, hypothalamus, dorsal medial thalamus are found. Diffusion-weighted imaging can be diagnostic early after injury and indicate injury before onset of necrosis. Mammillary body atrophy is an irreversible marker of chronic Wernicke encephalopathy and is best assessed on sagittal or coronal MRI.  Aggressive vitamin B1 therapy (100 mg/day, initially iv) should improve the neurological status of the patient. Improvement in ocular symptoms of Wernicke encephalopathy is universal and rapid, often within hours. Most patients with Wernicke encephalopathy will show complete recovery of extraocular motility, although a horizontal nystagmus may persist. Ataxia responds somewhat later, and only 40% of patients recover completely. The global confusional state also recedes, but 80% of patients with Wernicke encephalopathy are left with a residual memory disorder or a Korsakoff amnesic state. Most Korsakoff patients had initially evidence of Wernicke encephalopathy. Thus, both entities are commonly regarded as two facets of the same disease process, resulting from thiamine deficiency. Korsakoff syndrome, refers to an abnormality of mentation in which memory and learning are affected out of proportion to other cognitive functions, in an otherwise alert and responsive patient. Always search for hidden history of alcohol dependence.


Diphtheria polyneuropathy: Apparently 10% of adults vaccinated in childhood have insufficient residual immunity. Hence occasional outbreaks of diphtheria occur in these individuals. About 15% of patients diagnosed with diphtheria develop polyneuropathy. The disease presents in two waves first the bulbar phase and a second phase the polyneuropathy.  The earliest neurological symptom is always bulbar and consists of uni-or bilateral paralysis of the palate, appearing a median of 10 days after the onset of localized throat diphtheria (sore throat).  The voice becomes nasal, regurgitation of fluids through the nose on swallowing, the larynx becomes paralyzed, allowing inhalation and choking. 20% develop respiratory failure and will need intubation. Improvement of bulbar symptoms occurs at median 30 days from onset. Blurring of vision for near objects due to paralysis of accommodation with preserved pupillary reflexes and convergence. Facial and oculomotor paresis may occur. The second wave is characterized by generalized sensorimotor polyneuropathy affecting the limbs (limb weakness with paresthesias and distal loss of position sense and vibration) occurs in 90% at a median of 37 days from onset. 50% of patients may develop severe disability and being unable to walk, 30% develop impaired bladder control. Blood pressure swings or cardiac arrhythmias reflect either autonomic neuropathy or cardiomyopathy. Rarely, diphtheric hemiplegia (vascular or acute post-infective encephalitis) and spasmodic diphtheria (meningitis with opisthotonos) develop. The diagnosis is predominantly clinical and can be confirmed by throat cultures which are positive in 98%. CSF protein is usually elevated (50-200 mg/dl). The major differential diagnosis is GBS and MG. Survival has increased substantially. Limb symptoms persist in 80% of patients at 1 year. Diphtheric antitoxin given within 48h of the onset of the infection reduces the incidence and severity of the neuropathy.


Varicella zoster virus neuropathy: VZV infections are particularly likely in elderly and immunosuppressed patients and may affect 1/5th of all adults in life. Although shingles are easy to diagnose, less well-known are the neuropathic changes which occur. 50% of patients develop clinical evidence of paralysis (diaphragm, limb muscles, eye muscles, or facial muscles, bladder dysfunction and bowel ileus). Rarely meningoencephalitis occurs. However, 50% of patients have subclinical evidence of brainstem or spinal cord involvement on MRI and CSF is lymphocytic with VZV DNA in 60%. The feared long-term complication is post-herpetic neuralgia.


Non-systemic vasculitis (peripheral nervous system vasculitis): Develops as mononeuritis multiplex affecting the limbs, thoracic roots or the cranial nerves. Each mononeuropathy evolves over a few hours or days, producing muscle weakness, paresthesias and pain, and global sensory disturbance in the territory of the affected nerve. Tendon reflexes can be spared. Other patients present with symmetric or asymmetric distal axonal polyneuropathy which may be sensorimotor or pure sensory. The progression is usually fast. ESR is elevated in a minority of patients. CSF is usually normal. NCVs show axonal loss and denervation. Occasionally conduction block can be demonstrated. Sural or superficial radial nerve biopsy if electrophysiologically abnormal and combined muscle biopsy should be performed. Lack of paraspinal muscle involvement differentiates mononeuropathy multiplex from radiculopathy.


Systemic vasculitis: These occur in PAN, Churg-Strauss syndrome, and Wegener granulomatosis. The findings can be those of mononeuritis multiplex affecting small cutaneous sensory nerves in the fingers or feet, symmetrical distal sensorimotor neuropathy, brachial plexopathy, and radiculopathy. ANCA antibodies may present in the early stages of Wegener granulomatosis and PAN. cANCA antibodies may be positive in plasma and CSF  (90% sensitivity and 99% specificity) when systemic Wegener granulomatosis is present. Additional findings include, Raynaud syndrome,  hypergammaglobulinemia, mild liver-function abnormalities and ESR is severely increased. Although most patients have fever, weight loss or paranasal sinus involvement, 1/3 of patients with Wegener granulomatosis may have asymptomatic respiratory disease. 20-50% have neurological complications (mononeuritis multiplex, headache, sinusitis, orbital disease, hearing loss, cranial neuropathy or stroke). PAN may be associated with Hepatitis B and C, HIV, serum sickness, allergic reactions to drugs and toxins. pANCA antibodies may be found in PAN and Churg-Strauss syndrome. The latter is diagnostic distinctive by eosinophilia, late-onset rhinitis/asthma, mononeuritis multiplex and pANCA. Other conditions in which vasculitic neuropathy can occur RA, SLE, Sjögren disease, scleroderma and GCA. Other causes include hypersensitivity vasculitis (penicillin, cocaine and amphetamine), infectious forms (Hepatitis B) and malignancies. Diagnostic procedure are similar as those described for the non-systemic vasculitis. Corticosteroid therapy should not be delayed.


Cryoglobulinemia: 50% of patients with essential mixed cryoglobulinemia develop neuropathy. Peripheral neuropathy can be the sole presenting sign of cryoglobulinemia in about 15% of patients. Symmetric sensorimotor polyneuropathy is more common than mononeuritis multiplex. Painful dysesthesia and sensory loss in a stocking distribution with prominent restless legs, burnings, or formication are typical features. Prominent vasculitic purpura (leucocytoclastic vasculitis) and Raynaud phenomenon should suggest the diagnosis and can be confirmed by cold immunoagglutinin test on serum. Hepatitis C infections are common underlying conditions. Patients with both hepatitis C infection and cryoglobulinemia have more frequent higher alanine aminotransferase level, more frequent presence of rheumatoid factor, and a greater extent of histologic liver lesions than patients with cryoglobulinemia in the absence of Hepatitis C. Electrophysiologic studies typically confirm the neuropathy as an axonopathy, with EMG evidence of denervation and low amplitude nerve action potentials on nerve conduction studies. Sural nerve biopsy typically shows primarily axonal degeneration. Interferon-alfa is currently the only approved therapy for chronic hepatitis C. Significant response rates have been achieved  (up to 77%) with resolution or normalization of disease manifestations in skin, kidney, cryoglobulin levels, liver enzymes and some neuropathic complaints within 1-2 weeks.


Sensory perineuritis: This mononeuritis causes pain and numbness in the territories of individual cutaneous nerves. Severe pain in feet by standing or walking and Tinel sign is found. Initially the disorder may be relapsing and remitting, but symmetrical distal sensory loss may eventually appear. Trigeminal nerve may be involved. Tendon reflexes are preserved. Mixed motor and sensory nerve involvement exist. Nerve biopsy is diagnostic.


Migrant sensory neuritis of Wartenberg: The disease usually appears in midlife. Sudden pain in the territory of cutaneous nerves induced by movements, which results in stretching of the peripheral nerve produces electric shock sensation. After repeated episodes of pain, cutaneous sensation may be lost in the nerve territory for about 6 weeks. NCVs show reduced SNAPs in the affected nerve. The relapsing/remitting nature may initially suggest MS. The course is benign.


Diabetic polyneuropathy: The prevalence of neuropathy in diabetic patients is 30% in hospitals and 20% in the community. Two types of polyneuropathy may coexist: symmetric sensorimotor and autonomic polyneuropathy. 66% of IDDM and 59% of NIDDM patients have neuropathy (polyneuropathy accounts for almost 50% followed by CTS around 10%, visceral autonomic neuropathy in less than 10%. Only about 1/5th of diabetic patients have symptomatic disease while nearly 50% have abnormal NCVs. This neuropathy is significantly associated with diabetic retinopathy and nephropathy.

Diabetic small-fiber sensory polyneuropathy: This is most prevalent in IDDM of more than 20 years duration, and in those with AHT or poor glycemic control. The majority of patients present initially with relative symmetric sensory symptoms including paresthesia, burning and lancinating pain in the legs with stocking distribution. Pain and temperature sensation is affected, vibratory sensation and joint position sense are lost in the toes. Positive Romberg sign with sensory gait ataxia may be found. Ankle jerks are lost, while others are preserved. Autonomic features may include warm dry foot with hard vulnerable skin with cracking. Neuropathic joints may develop. Distal muscle weakness (with atrophy) is unusually except in longstanding cases. Since it is often the first manifestation of diabetes, early detection is important (impaired glucose tolerance using oral glucose tolerance testing (2-hour glucose; 140-199 mg/dl = IGT, > 200 mg/dl = diabetes)) and NCVs (reduced or absent SNAPs with normal motor NCVs). However in patients with selective loss of pain and temperature sensation this may be hard to detect. Sural biopsy are usual diagnostic. Skin biopsy may be helpful (3 mm punch skin biopsy from distal leg and proximal thigh. Staining with protein gene product 9.5 and measure intraepidermal nerve  fiber density). Optimal control of glycemia improves vibration sense. Extreme insulin therapy may cause distal symmetric motor peripheral polyneuropathy particularly affecting the arms.

Diabetic autonomic neuropathy: 1/6th of all IDDM patients have autonomic peripheral neuropathy, but few have real symptoms (commonly abnormal sweating or diarrhea, less frequently postural hypotension, vomiting, micturition difficulties, bladder atony with infections, impotence and retrograde ejaculation). Very often it coexists with small-fiber sensory polyneuropathy. Symptomatic autonomic neuropathy predisposes patients to sudden death during anesthesia, to cardiac arrhythmias, and reduced awareness to hypoglycemia. The diagnosis can be made by autonomic function testing.

Distal polyneuropathy: Distal, symmetrical, primarily sensory neuropathy is the commonest form of chronic neuropathy in diabetes. The lifetime incidence is estimated at 37-45% in type 2 diabetes and 54-59% in type 1 diabetes. The clinical presentation consists of distressing numbness and paresthesias in the feet and lower legs, worse at night. The pain is often reported as superficial presenting as allodynia, sharp, stabbing, or burning pain in the feet. The ankle and knee jerks are absent. Trophic changes may occur. There is generally a family history of diabetic polyneuropathy and obesity is commonly found. Tendon reflexes and distal sensation are reduced. Autonomic dysfunction (orthostatic hypotension) may be present. Fasting blood glucose is >126 mg/dl (7 mmol/L) and 2-h glucose tolerance test is abnormal (>200 mg/dl). EMG and NCVs are abnormal.

Proximal diabetic radiculopathies: There are two distinctive forms of radiculopathy in diabetic patients; the painful asymmetric radiculopathy often referred to as "diabetic amyotrophy" and the painless proximal symmetric amyotrophy. The diabetic amyotrophy is most commonly observed in NIDDM patients in their 6th or 7th decade. In contrast to diabetic polyneuropathy, it seldom accompanies diabetic retinopathy and nephropathy. The initial manifestation is usually subacute evolving lumbar pain originating from the back or hips, and irradiating in an often asymmetric pattern to the anterior thigh or knee. The pain has usually a deep, aching character with superimposed lancinating jabs, and often most severe at night. Pelvic girdle and thigh muscle weakness and atrophy are evident, but mainly affecting the quadriceps muscle and developing over the next few days or weeks. The knee jerks are lost. Despite the unilateral onset, bilateral weakness eventually occurs in 50% of patients. The plantar responses may be extensor! Upper extremities are rarely affected. Deep and superficial sensation may be intact or mildly affected. The neuropathy is associated with profound weight loss. Femoral NCV is delayed. CSF is slightly elevated. Improvement of the condition is usually seen after some months (or years). Only 20% of patients have complete recovery of muscle strength. 1/5th of patients experience recurrence and often affecting the opposite limb. Differential diagnosis (even in diabetic patients) should include retroperitoneal hematoma, carcinomatous meningitis, neoplasia and sarcoidosis. Against the diabetic amyotrophy, there is the painless proximal symmetric amyotrophy associated with leg weakness, wasting and progressive loss in reflexes. The iliopsoas, quadriceps, and hamstrings are affected in varying degrees. The shoulder girdle muscles are less frequently affected. There are generally no associated sensory abnormalities, and if present are distal, symmetric, and mostly mild in degree. Important to mention is that clinically there may be a great overlap between these two forms of radiculopathy.

Diabetic mononeuritis multiplex: This painful unilateral or asymmetrical multiple neuropathy tends to occur in elderly with mild diabetes or unrecognized diabetes. It tend to occur during periods of transition, when severe hyperglycemia or hypoglycemia arises, following the initiation of insulin therapy or in association with rapid weight loss.

Diabetic mononeuropathy: Painful oculomotor nerve palsies, often sparing the pupil are common in older diabetics and resolve spontaneously. Several peripheral nerves are vulnerable to compression.

Diabetic truncal neuropathy: Attacks of truncal pain and sensory loss affecting one or more thoracic roots can occur. It typically occurs in the 5th - 7th decade in NIDDM and is associated with heavy weight loss. Focal paralysis of the abdominal wall muscles may be seen. EMG shows denervation of paraspinal muscles. Recovery is spontaneous but may take months.


Uremic polyneuropathy: 50% of patients with end-stage chronic renal failure have clinical or electrophysiologic evidence of polyneuropathy. Uremic polyneuropathy develops gradually and occurs with glomerular filtration rates below 10 ml/min. In contrast to the underlying causes of renal failure, which are often resulting in focal or demyelinating polyneuropathy, uremic polyneuropathy is axonal in nature. Restless legs (burning paresthesias, itching sensation) are often the initial manifestation, followed by muscle cramps and fatigability and, finally, muscle distal weakness and atrophy. Autonomic features are impotence and postural hypotension (most marked at times of fluid removal by dialysis). The earliest objective signs are loss of vibration at the toes and absent ankle jerks. NCVs indicate axonal degeneration of motor and sensory fibers. Renal transplant greatly improves the condition. Occasionally an acute uremic polyneuropathy may develop that resembles GBS. Most patients are diabetics in stable end-stage renal failure that is being treated with peritoneal dialysis. NCVs may show demyelinating features and raised CSF protein.


Hypothyroidism: 50% of patients with myxedema develop polyneuropathy consisting of paresthesias, lancinating limb pains, or muscle cramps. Minor distal sensory changes and slowly relaxing tendon reflexes are the only abnormalities on physical examination. Nerve biopsy may show segmental demyelination. Treatment usually resolves the symptoms. Carpal and tarsal tunnel syndromes are common.


Acromegaly: Both polyneuropathy and CTS are common in acromegaly. The polyneuropathy is insidious in onset, causing distal paresthesias, areflexia, distal muscle weakness, and multimodal sensory disturbance. There may be palpable nerve enlargement. NCVs are reduced.


Primary biliary cirrhosis: This may present with a distal sensory polyneuropathy. Sural nerve biopsy may help to confirm the diagnosis.


Idiopathic hypereosinophilia: Symmetric sensorimotor peripheral polyneuropathy due to axonal degeneration develops in 1/10th of patients suffering from this disease. 


Critical illness polyneuropathy (CIP): 70-80% of patients with severe sepsis and multiorgan failure develop CIP within 72 hours of onset of septic shock. it is often associated with CIM. CIP is typical acute symmetric axonal neuropathy, which develops during therapy of severely ill patients and remits spontaneously once the critical condition has been managed. Hence the condition is monophasic and self-limiting. The neuropathy only comes to light while weaning from the ventilator. Muscle atrophy, severe flaccid tetraparesis, with hardly any movements on pain stimulation are characteristic of this condition. Cranial nerves and autonomic function are spared. Tendon reflexes are spared in 30% of patients and is not an argument against the diagnosis. The CMAP and SNAPs are reduced (within 3 days of admission for sepsis) with no signs of demyelination (hence a pure axonal neuropathy) and EMG reveals limb muscle denervation. Reduced amplitudes are predictive of increased mortality. Reductions in CMAP or SNAP of at least 30% in > 2 nerves during the 1st week of sepsis are more likely to acquire neuromuscular disease. The CSF is normal in protein. The mortality is high and those who recover neurologically take over 3 - 6 months. GBS and critical illness myopathy (occurring with asthma treated with non-depolarizing neuromuscular blocking agents or high-dose steroids and characterized by elevated serum CK levels), preexisting conditions such as botulism, organic phosphate poisoning, porphyria, MND, MG belong to the differential diagnosis. In patients undergone transplantation or chemotherapy, neuropathy should be considered. Other considerations are prolonged neuromuscular blockade.


Alcoholic polyneuropathy: Besides pressure palsies often occurring after periods of stuporous immobility, alcoholics are prone to develop polyneuropathy.  The onset is often insidious and presents with distal symmetric dominant sensory-dominant polyneuropathy confined to the legs. Painful sensations with or without burning with burning quality represents the initial and major symptom. Other manifestations are dysesthesias, paresthesias or sensory ataxia. Autonomic features may be present (commonly abnormal sweating or diarrhea, less frequently postural hypotension, vomiting, micturition difficulties, impotence and retrograde ejaculation). Symptomatic autonomic neuropathy predisposes patients to sudden cardiovascular death due to cardiac arrhythmias. One should always be suspicious about the nutritional status in alcoholics (vitamin B1 etc.). Electrophysiological studies show axonal neuropathy predominantly affecting the sensory nerves. Progression is gradual continuing over months or years. Abstinence reveals gradual improvement in the polyneuropathy. Rapidly progressive polyneuropathy resembling GBS but without raised protein or slowed NCVs can occur in alcoholics.


Subacute combined degeneration of the spinal cord (SACD): Vitamin B12 deficiency leads to SACD. High-risk groups for the deficiency syndrome include the elderly, defective intrinsic factor production by gastric parietal cells (pernicious anemia), patients taking ulcer medications over long periods, heavy abuse of nitrous oxide, patients with AIDS, vegetarians, patients who have undergone stomach resection or small bowel resection, or both, and patients with dementia. The onset of symptoms is usually insidious, with paresthesias in the hands and feet present in the majority of patients. Sensory peripheral neuropathy can be the sole manifestation of B12 deficiency. Paresthesias in the feet and distal loss of all modalities of sensation with loss of ankle jerks are observed. Symptoms improve after therapy with B12. The next most common complaints include weakness and unsteadiness of gait. Cerebral symptoms may occur and can include confusion, delusions, hallucinations, mental slowing, and depression. Loss of position or vibration sense is the most common abnormality. Motor impairment may range from only mild clumsiness to a spastic paraplegia. Visual impairment can be seen; ophthalmological exam may show bilateral visual loss, optic atrophy, and centrocecal scotomata. Brainstem or cerebellar signs or even reversible coma may occur. Hematological abnormalities, including hypersegmentation of polymorphonuclear cells and a macrocytic anemia, can be seen; however, they may be completely absent at the time of neurological presentation. Current state-of-the-art testing uses serum cobalamin levels as a screening test, and the Schilling test, serum or urine methylmalonic acid and homocysteine determinations as confirmatory tests. A Schilling test detecting impaired intestinal absorption of vitamin B12, should be performed if there is enough clinical suspicion for the disease, and may reveal low vitamin B12 absorption even when the serum level is normal. The presence of circulating antibodies to parietal cells in many of these patients suggests an underlying autoimmune disorder. MRI reveals confluent leukoencephalopathy, even in the absence of anemia or myelopathy. VEP and SEP are frequently abnormal. SNAPs are absent or reduced in about 80% of patients and motor NCVs show axonal and demyelinating features. A typical regimen consists of intramuscular vitamin B12 injections of 1 mg twice weekly for 2 weeks, followed by monthly injections of 1 mg. For patients whose Schilling test demonstrates malabsorption of vitamin B12, monthly 1 mg injections should be continued on a lifelong basis. There is no evidence that overdosing can speed neurologic recovery; adverse reaction to high doses of vitamin B12 is unknown.


New variant Creutzfeldt-Jacob disease (nvCJD): Unlike for CJD, the mean age of onset of nvCJD is much younger (26-28 years) and the duration of the illness is longer (median duration 13 months, ranging from 6 to 39 months). Early signs of nvCJD can be either psychiatric and/or sensory symptoms. Psychiatric symptoms are dysphoria, withdrawal, anxiety, depression, apathy, weight loss, hallucinations, suicidal ideation and mild insomnia. Sensory symptoms consist of foot pain, dysesthesia/paresthesia of hands and face, legs, persistent cold feet, hemidysesthesia, hyperesthesia and pain in the lower limbs. Subsequently (usually within 4 months), patients develop overt neurological dysfunction with prominent sensory symptoms (if not yet present) memory impairment, ataxia dysarthria and rapidly progressive dementia, involuntary movements, incontinence and akinetic mutism. EEG is generally non-specific and not characteristic as in CJD. CSF analysis may show slight increase in protein. Testing for CSF 14-3-3 proteins is not useful in nvCJD. MRI shows bilateral increased pulvinar signal on T2-weighted images.  Prion protein (PRNP) gene analysis shows methionine-methionine genotype at codon 129. Abnormal PRNP may be found in the tonsils of individuals affected with nvCJD.


Mononeuritis multiplex: In its subacute form mononeuritis multiplex may be caused by diabetes mellitus, uremia (occasionally subacute), beriberi, vasculitis (PAN, Churg-Strauss syndrome, hypereosinophilic vasculitis, RA, Sjögren syndrome, SLE, Wegener granulomatosis and isolated peripheral nervous system vasculitis), mixed cryoglobulinemia, sarcoidosis, HNPP, ischemic neuropathy with peripheral vascular disease and infectious causes (HIV, Lyme disease, leprosy, hepatitis C). More chronic forms of this form of neuropathy include uremia, beriberi, diabetes, connective tissue diseases, amyloidosis, leprosy, hypothyroidism, paraneoplastic syndromes (carcinoma, leukemia, lymphoma and myeloma), CIDP, paraproteinemias (plasma cell dyscrasia, MGUS, angioimmunoblastic lymphadenopathy with dysproteinemia and Castleman disease) and benign sensory forms in the elderly.


Hepatitis C virus neuropathy: Extrahepatic manifestations of hepatitis C virus infection occur in 40-75% of chronically infected patients and include mixed cryoglobulinemia related manifestations such as chronic sensory polyneuropathy, multineuropathy, and encephalopathy, and non-cryoglobulinemic symptoms consisting of anterior optic neuropathy and restless legs syndrome with small-fiber neuropathy. Axonal symmetric distal neuropathy is almost invariably present. The neuropathy is painful and affects distal part of the limbs. Mixed cryoglobulinemia is detected in most patients and is significantly associated with vasculitis (leucocytoclastic vasculitis). Almost 60% of hepatitis C virus patients with neuropathy have circulating mixed cryoglobulinemia, IgM RF, polyclonal IgG and hepatitis C virus RNA.


Acute autonomic polyneuropathy or acute pandysautonomia: This is an acute auto-immune disorder affecting the autonomic nervous system and manifested by postural hypotension, impairment of sweating, lacrimation and bladder and bowel function. The diorder develops over a week or a few weeks. Patients may complain of paresthesias and have absent tendon reflexes. CSF analysis is normal or shows slightly increased protein. Antibodies against ganglionic acetylcholine receptors have been found in 50% of patients.


Idiopathic peripheral facial palsy (Bell palsy): The incidence of Bell palsy is 2-3‰. Retroauricular pain usually precedes the paralysis by 1 or 2 days. Almost 50% show maximal paralysis in 2 days with a nadir by 5 days. Recovery takes weeks - 2 month. Ramsay-Hunt syndrome (zoster around the ear, acute peripheral facial palsy, and symptoms involving the VIII cranial nerve) is caused by a reactivation of VZV. The same virus causes acute peripheral facial palsy without skin lesions (zoster sine herpete). Favorable prognosis is indicated by preserved action potential preserved R1 or reappearance of R1 after 3 weeks. About 15% of patients will have permanent sequelae. The facial palsy associated with Ramsay-Hunt syndrome is more severe and has a lower recovery rate than that of Bell palsy. The diagnosis of Ramsay-Hunt syndrome is relatively easy in the presence of typical skin rash. However in cases without skin rash a PCR DNA test from the CSF may be helpful. A combination of acyclovir (4000 mg daily for 5 days) and prednisone (60 mg/day for 4 days) provide a 100% cure rate if started within 3 days after the onset.


Restless legs syndrome (RLS): Prevalence estimates of RLS for the general population vary considerably and range between 2.5-15% depending on the age. There is an increased tendency with age. Early (< 45 years) and late-onset RLS differ etiologically. Two forms of RLS exist: one is triggered by painful dysesthesia associated with small sensory fiber loss, has later onset, and no family history; and one without involvement of small sensory fiber loss, with an earlier onset age, positive family history and no pain. Leg paresthesia/dysesthesias inducing akathisia, worsening or being exclusively present at rest during the evening or night with at least partial or temporary relief by activity e.g. walking around. RLS often leads to nocturnal insomnia and daytime sleepiness. Reduced ferritin and elevated CSF transferring have been found. CSF hypocretin-1 levels may be increased in evening samples, particularly in patients with early-onset RLS. Most cases are idiopathic (60%), and have a positive family history in 60% of cases, indicating an autosomal dominant mode of inheritance. Secondary causes have been reported; myelopathy, uremic and other polyneuropathies, iron deficiency, hepatitis C and vitamin deficiencies. Levodopa/carbidopa is useful on an intermittent basis, since long-term therapy may worsen RLS. Dopamine agonists (first step): pramipexole and ropinirole are the treatment of choice in moderate to severe RLS (pramipexole 0.125 mg to 1.0 mg nocte; ropinirole 0.25 mg to 1 mg nocte, bid or tid). Opioids (codeine 15-60 mg od nocte, hydrocodone, oxycodone 5 mg nocte an repeat during night, propoxyphene 200 mg od nocte and tramadol) may be used on an intermittent basis. Benzodiazepines (clonazepam 0.5-2.0 mg od nocte, temazepam 15-30 mg od nocte) are useful as rescue therapy, and may help improve sleep. When dopamine agonists fail, anticonvulsant therapy can be considered such as carbamazepine and gabapentin (300-1,800 mg/day). This therapy is particular useful with coexisting polyneuropathy. Iron is recommended in those patients with ferritin levels lower than 50 microgram. In such cases of underlying iron deficiency 325 mg ferrous sulphate (plus 100 mg of vitamin C) should be given tid. Clonidine may be of use in patients with concomitant hypertension.


Acute sensory ataxic neuropathy (ASAN): Acute onset of sensory ataxia, loss of deep tendon reflexes, and impaired vibratory and joint position sensations are the characteristics of ASAN. Some patients have a history of infections. Anti-GD1b IgG antibodies may be found during the acute phase.


Primary amyloidosis: Neuropathy develops in 30% of cases and starts rarely before midlife. Peripheral neuropathy is the presenting symptom in 10% of patients with primary amyloidosis and those patients tend to have the longest survival. The features are those of chronic, slowly progressive, axonal polyneuropathy which is distal and usually symmetric. The first signs are those of sensory impairment (pain and temperature sensations and numbness of the limbs and spontaneous burning or lancinating pain) and less often autonomic. The lancinating pain can be very focal and affect one finger for a few weeks. Motor weakness and areflexia occurs later in the course of the disease. Autonomic dysfunction includes pupillary reactions, gastrointestinal symptoms, impotence, incontinence and postural hypotension. Atypical patterns include mononeuritis multiplex, motor-predominant forms with demyelinating features, MND, asymmetric lumbosacral polyradiculopathy or plexopathy, and oculomotor, trigeminal and facial neuropathies. In addition to neurologic features there might be macroglossia, proteinuria, hepatosplenomegaly, lymphadenopathy (30%), nephrotic syndrome and paraproteinemia (IgG monoclonal gammopathy (levels usually <2000 mg/dl)). Occasionally muscular stiffness, hypertrophy and weakness may occur. CSF protein is often raised. NCVs show axonal degeneration neuropathy. MRI scan may visualize thickening of plexus, roots or nerves. The diagnosis can be made by nerve, lymphadenopathy or rectal biopsy.



Chronic inflammatory demyelinating sensorimotor polyneuropathy (CIDP): This slowly progressive steroid-dependent polyneuropathy can occur at any age (mean age of onset in the 5th decade). The clinical presentation is that of progressive/relapsing and remitting muscle weakness present for more than 2 months, symmetrical proximal and distal extremity weakness and hyporeflexia. May resemble GBS with the difference that there is no recovery but rather deterioration. In women, relapses are particularly associated with 3rd semester of the pregnancy or immediately postpartum. Up to 30% of patients have a history of viral infection or vaccination. The majority of patients present with relative symmetric numbness and tingling (sensorimotor neuropathy with (sometimes painful) paresthesia), loss of vibratory sensation and joint position sense with positive Romberg sign as common early manifestations. Limb weakness is usually affecting proximal, muscles more than distal musculature. Both upper and lower extremities are involved, although the legs are usually affected more severely. Deep tendon reflexes are absent or depressed. Neck flexor weakness distinguishes CIDP from most other neuropathies. Sensory findings are typically mild and often include impaired touch and vibratory sensation, with less involvement of small-fiber sensation (pain and temperature). Pure motor or sensory forms do exist. Deterioration over > 8 weeks is a distinguishing criterion from GBS. Cranial nerves (diplopia, dysphagia, facial or masticatory muscles, papilledema) are affected in about 15% of patients. A coarse, irregular action tremor, often seen in paraproteinemic neuropathy, may occur and may be related to a CNS equivalent mimicking neuroradiologically MS. Albuminocytologic dissociation (elevated CSF protein >45 mg/dl in the absence of a high cell count <10) is characteristic of CIDP. An elevated IgG index and IgG synthesis rate is consistent with the immune-related nature of CIDP. An elevated Q-albumin shows an impairment of the blood-brain barrier, which in CIDP is at the level of the inflamed nerve root sheaths within the thecal sac. The hallmark of the disorder is: 1) reduction of in NCV of less than 90% of lower limit of normal (e.g. <45 m/s in UL and 36% in LL) if the amplitude exceeds 50% of the lower limit of normal; or less than 80% of the lower limit of normal (40 m/s in the UL and 32 m/s in the LL), if the amplitude is <50% of the lower limit of normal in >2 nerves; 2) partial conduction block (<15% change in duration between proximal and distal sites) or abnormal temporal dispersion (>15% change in duration between proximal and distal sites) in > 1 nerve; prolonged distal motor latencies in >2 nerves  (>130% of normal); 3) proximal or distal amplitude ratio of <0.7; 4) absent or prolonged (125% of the upper limit of normal e.g. 36 m/s UL and 63 m/s LL) F-wave latencies in >2 nerves. In addition, distal CMAP duration > 9 msec for any of four motor nerves (ulnar, median tibial or peroneal nerve) increases the diagnostic sensitivity. SNAP are usually reduced or absent. Despite these criteria diagnostic difficulties may arise with borderline cases. CSF protein is normal or elevated (> 100 mg/dl). MRI findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy include enhancement (hypertrophy) of cervical roots, brachial plexus or the cauda equina, and may enhance after the administration of gadolinium. The cervical cord area on MRI is significantly smaller in probably due to axonal loss. Sural nerve rarely adds to the diagnosis. A proven diagnosis of CIDP is an excellent chance of recovery with immunosuppressive therapy. CIDP can be associated with a variety of underlying disorders including: malignancies (lymphoma, Castleman disease, carcinoma), autoimmune disorders (SLE, temporal arteritis, RA, MCTD, amyloidosis etc.), infections (HIV infection before developing AIDS, hepatitis C), renal disorders or endocrine disorders (diabetes, thyroid disorders).  Suspicion of such relation should be raised when; (1) the neuropathy evolves rapidly with unusual features (e.g. extensive cranial nerve involvement or neuropathic pain), (2) deterioration continues despite immunosuppressive therapy. A useful differential diagnostic tool between MMN and CIDP is the presence in MMN of  GM1 ganglioside antibodies (in 40-80%), normal CSF protein levels, and sometimes IgM monoclonal gammopathy. Furthermore MMN and pure motor forms of CIDP differentiate from CIDP by the lack of response to steroids and even clinical deterioration. Treatment (oral steroids, plasma exchange, iv immunoglobulin) should not be postponed until it is clear whether a patient suffers from GBS or CIDP. Prednisolone is given as 60-120 mg (1 to 1.5 mg/kg/d) for 2-4 weeks and then switched to a single dose on alternate days after 2-3 months in patients who respond favorably and then continued until clinical improvement plateaus. Then prednisolone is tapered by 5-10 mg every 2-4 weeks. When deterioration occurs IV immunoglobulin therapy or azathioprine should be added. After starting steroid therapy, there may be a lag time from the onset of therapy to first signs of clinical improvement of 1-4 weeks, occasionally up to 5 months. Over 60% of patients respond to steroids. IV immunoglobulin infusions (starting dose 0.4 g/kg for 5 days, maintenance dose commonly tapered to total of 0.4 g/kg) are as effective as steroids or plasmapheresis, but their cost and their short-lived response (commonly 2-8 weeks) make them to an disadvantage. Over 80% of patients respond to IVIg and improvement occurs usually after 2 weeks. Azathioprine (3 mg/kg) in a single dose can be considered when previous measures fail. CBC and liver function tests should be evaluated before and during this treatment. The drug has a steroid-sparing effect in steroid-responsive patients. Without therapy, CIDP is fatal in up to 10% of patients. Although 95% of patients will show initial improvement following immunosuppressive therapy, the relapse rate is high. 64% improved and are able to return to work and 11% become bedridden or wheelchair bound.


Chronic idiopathic sensory neuropathy (CISN): This is basically a sensory form of CIDP with limb ataxia, numbness and pain, loss of proprioception, normal muscle strength but generalized areflexia. Despite this, motor NCV is slowed. SNAPs are absent. CSF protein is raised. Demyelination can be found on sural nerve biopsy. Deterioration is seen over months or years. Obviously, CANOMAD, paraneoplastic sensory neuropathy, sensory ganglionitis associated with Sjögren disease, vitamin E deficiency and CIAP are to be considered as differential diagnosis.


Acute idiopathic demyelinating polyneuropathy or Guillain-Barré syndrome (GBS): The incidence is in the order of 1-3/100,000 people per year. The mean age of onset is around 40 years with a bimodal distribution, one in the 3 rd and one in the 6th decade. About 90% of patients present with clinical preceding infections (influenza-like, respiratory (40%), gastrointestinal (20%)) 1- 3 weeks before the onset of neurologic symptoms. In 70% serologic positive infections are detected (Campylobacter jejuni, CMV, EBV, Mycoplasma pneumoniae, HIV, Lyme disease). The disease presentation can be different according to the type of organism involved: Campylobacter infections are associated with preceding diarrheal illness in 70% and present as a pure motor disorder (acute motor axonal neuropathy) with more severe course. CMV occurs in younger patients with a high occurrence of respiratory muscle weakness, cranial nerve involvement, and sensory involvement. GBS can occur irrespective of treatment of the underlying campylobacter infection. Cases of GBS have been reported following surgery or trauma, pregnancy, connective tissue diseases, medications (d-penicillamine), swine influenza virus vaccination or with underlying Hodgkin lymphoma. HIV-induced GBS occurs around the time of the primary infection. HIV antibodies may not be present and P24 antigen assay may be required to confirm the diagnosis. Neurologic symptoms develop 1 - 4 weeks after the preceding infection. The first neurological features are paresthesias in the toes, simultaneously or shortly thereafter followed by profound progressive motor weakness of more than one limb. In addition 50% of patients develop severe back and buttock pain which resolves as recover starts. Impaired posterior column functions and mild to severe sensory nerve involvement can be found. Symmetric muscle weakness with areflexia affecting most prominently the trunk musculature usually starts in the legs and ascends to the arms. Maximal muscle weakness (tetraparesis) develops within two weeks of the onset of neurologic symptoms and as per criterion symptom progression should not go beyond 4 weeks. Those patients who become bed-bound and ventilator-dependent within 5 days tend to have the most prolonged disability and sequelae. 50% of patients develop cranial nerve palsies, most commonly facial, bulbar, masticator and ocular muscles. Several degrees of respiratory muscle involvement may occur; 25% of patients need assisted ventilation. All patients with vital capacity <1L will need ventilation. Cardiac arrhythmias (10%), wide fluctuations in blood pressure and heart rate, episodes of facial flushing, pupil abnormalities, patchy anhidrosis, paralytic ileus or urinary retention. These are generally associated with poor prognosis. Other uncommon neurologic manifestations may be papilledema, optic neuritis and pyramidal signs and probably indicate associated ADEM. In 3% of cases GBS may be relapsing each time preceded by infections or vaccinations and needs to be differentiated from CIDP. Variants of GBS exist: bifacial paresis, pharyngeal-cervical-brachial weakness, MFS, paraparesis variant, autonomic form. CSF shows in 80% of patients typical albuminocytologic dissociation but may be absent the first few days (protein levels >2g/l with no pleocytosis). The CSF protein content is highest during the 1st and 3rd week after the onset of symptoms.  Interestingly, in HIV-induced GBS CSF may show pleocytosis (20-30 cells/mm3). Serum IgM antibodies may be detected and stool cultures may be positive in case of Campylobacter jejuni enteritis. Antiganglioside polyclonal IgG antibodies (GM1, GM2, GD1a, GQ1b) are found 60% of patients. Mild forms are characterized by striking absence or 10 times lower frequency rate of these findings, e.g. antiganglioside antibodies are almost absent in mild forms of AIDP. Earliest abnormalities on needle examination are reduced recruitment. Abnormalities in motor nerves are generally found during week 3, while those for sensory nerves in week 4. The neurophysiologic criteria requires 3 of the following 4 features: (1) reduction in NCVs in > 2 motor nerves, (2) conduction block or abnormal temporal dispersion in > 1 motor nerves, (3) prolonged distal latencies in > 2 motor nerves, (4) absent or prolonged F wave latencies in > 2 motor nerves. Improvement in motor amplitudes corresponds to clinical improvement, while conduction velocity and clinical examination are not closely related to one another. MRI might show enhancement of the cauda equine roots after gadolinium administration. Despite intensive efforts mortality is around 10%. Elderly succumb to cardiac complications, pulmonary embolism or chest infections. In the survival group 60% make full recovery. Factors of poor predictive outcome are: age >60 years, preceding diarrheal illness, development of severe paralyses within 5 days of the onset, respiratory failure requiring ventilation, and mean distal CMAP < 20% of normal. Observation of the patient is essential. When signs of oropharyngeal weakness, inability to walk or reduced vital capacity (<1L) occur plasma exchange or iv immunoglobulin should be considered. Both proved to have similar effectiveness. Relapse may be observed (days or 3 weeks) in 5-10% of patients who initially improved on either therapy. Mortality is up to 5%. GBS should be differentiated from acute spinal cord compression (cervical myelopathy), transverse myelitis, basilar artery thrombosis, HIV myelitis (usually at time of seroconversion and is associated with CSF pleocytosis), MG, acute intermittent porphyria, poliomyelitis (fever at onset and CSF pleocytosis), acute toxic neuropathies, botulism, tick paralysis, CIP and diphtheric neuropathy.


Critical illness myopathic syndromes (CIM): This type of myopathy occurs typically in intensive care units and manifests itself one week to 10 daysafter the onset of the critical illness. Common risk factors are long duration of immobilization, hyperglycemia, hypoalbuminemia, use of steroid  and/or neuromuscular blocking agents (NMBA), hormonal factors, sepsis, systemic inflammatory response syndrome and APACHE score III. These syndromes have a clinical presentation which is very similar to its neurogenic equivalent, the CIP. They can be divided on the basis of their pathological characteristics into three forms: the diffuse non-necrotizing myopathy (also known as the classical 'critical illness myopathy'), the thick filament myopathy and the acute necrotizing myopathy. The diffuse non-necrotizing form reveals often little abnormalities with normal serum CK levels and mild EMG abnormalities. This form is often associated with CIP. The thick filament myopathy is commonly observed in patients with severe intractable asthma and transplant recipients receiving high doses of corticosteroids and which have in addition been treated with NMBA for more than 3 days. Serum CK are elevated and myoglobinuria is often present. Acute necrotizing myopathy is associated with high serum CK levels and rhabdomyolysis. The severe muscle weakness becomes evident when the systemic illness subsides, and slows weaning from the ventilator. Tendon reflexes are normal or reduced and there may be confounding CIP. Muscle biopsy may be helpful in the diagnosis. Recovery may take weeks. 

Acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) variants of Guillain-Barré syndrome: Patients with AMAN have a rapid progressive ascending symmetric weakness beginning in the lower limbs (distal weakness most prominent) and plateau on average at 6 days. 30% of patients will need ventilation. Cranial nerves involvement is less common. Autonomic dysfunction occasionally occurs. Sensory symptoms almost never occur. A rapid and dramatic fall in CMAP (AMAN) and/or SNAP (AMSAN) amplitudes without electrodiagnostic evidence of demyelination (normal distal motor latency and conduction velocity). AMAN and AMSAN are highly associated with Campylobacter jejuni infections (GM1 ganglioside polyclonal IgG antibodies: anti-GM1, GD1a, and GD1b). AMAN is more likely to be associated with rapid progressive weakness, often with respiratory failure and usually good recovery. Although some cases are fatal, recovery is similar to AIDP. The course of AMSAN is typically fulminant and the prognosis is generally poor. Median time to regain ability to walk 5 meters with assistance is 1 month. Iv immunoglobulin are less effective than in GBS.

Sensory variant of Guillain-Barré syndrome: Profound limb sensory loss, particularly posterior column dysfunction with ataxia and little or no weakness with preserved or absent reflexes. NCV shows demyelinating sensorimotor polyneuropathy.


Lyme disease: Neurologic abnormalities occur in 10 to 20% of patients with Lyme disease starting a few weeks to several months after the tick bite. Human infections are usually seasonal (summer) and occur in patients who have been in woodlands populated by rodents, squirrels and deer. History of tick bite is absent in over 50% of patients. The most common early neurologic manifestations are aseptic meningitis, meningoencephalitis following erythema migrans by 2-10 weeks, often associated with cranial neuropathy, motor or sensory polyradiculoneuritis (typically cauda equina neuritis) and peripheral neuropathy.

Lyme meningitis presents like classical meningitis with about 2/3 of patients having systemic manifestations, including malaise, fatigue, myalgia, arthralgias and weight loss. Untreated the duration of symptoms ranges from 1-9 months and the patients experience recurrent attacks of meningeal symptoms lasting several weeks. Other manifestations may include somnolence, emotional lability, depression, memory impairment, and behavioral abnormalities. Cranial neuropathies, particularly bilateral facial nerve palsy,  transverse myelitis, spastic paraparesis, disturbances in micturition, Babinski sign are also observed during this stage. 

Cranial neuritis - uni- or bilateral facial palsy with subjective sensory disturbance occurs often during the early weeks of Borrelia infection. Recovery can be spontaneous, but oral antibiotic therapy should be instituted.

Polyradiculopathy - Shooting pain in the territories of the affected nerve roots with loss of reflexes and sensorimotor abnormalities in the limbs may last months but recovers spontaneously. Sharp chest-wall pain reflect involvement of the thoracic nerve. 50% of patients have also facial palsy.

Peripheral neuropathy - mononeuritis multiplex, polyneuropathy, and acute brachial neuralgia may all occur in Lyme disease and can be associated with any of the other neurologic abnormalities. Mononeuritis multiplex and acute brachial neuralgia may occur within the first few months of the infection. Polyneuropathy is a manifestation of post-treatment Lyme disease syndrome (PTLDS).

Late neuroborreliosis or PTLDS develops weeks/months or years after disease onset and may cause symptoms of mild encephalopathy, such as memory impairment and concentration deficits, or chronic mild, multifocal, patchy axonal polyneuropathy manifested as distal intermittent paresthesias or radicular pain with preserved reflexes and motor function. Other non-focal symptoms are headache, mild depression, irritability, fatigue, myalgia and sleep disturbances. CSF shows striking lymphocytic pleocytosis (up to 700 cells/mm3), but may be normal in isolated facial palsy or peripheral polyneuropathy. CSF protein is elevated (up to 600 mg/dL) and CSF glucose normal or decreased in long-standing disease. Although this patients with Lyme encephalopathy often have normal findings on CSF analysis. Culture from CSF are very disappointing (5% success rate). NCVs show reduced and slowed SNAPs, and sometimes increased distal motor latencies. MRI on PTLDS is often normal or difficult to differentiate from MS. The diagnosis is based on the demonstration of elevated serum or CSF IgM or IgG antibody titers to B. burgerdorfi (ELISA). The sensitivity/specificity of ELISA for B. burgerdorfi varies from 58% to 92%, improving with longer duration of disease (> 10 months). However this test is very insensitive with respect to the stage of the disease. Furthermore if serum titers are positive, CSF titers are not necessary. Serum titers should be repeated if there is high suspicion of Lyme disease. Positive or equivocal ELISA results should be confirmed by Western blot to rule out a false-positive result. The Western blot has a high sensitivity and specificity for IgG. The Western blot has poor specificity earlier after infection (less than 10 months), and high cross-reactivity with any other immune responsive disorder.