Neuromuscular Disorders

Identifying the pattern of weakness for the major muscle disorders is important to steer the diagnostic workup. The following phenotypic patterns are recognized:

Ptosis with ophthalmoplegia occurs in oculopharyngeal dystrophy, mitochondrial myopathies, neuromuscular junction abnormalities (myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulism), and HIBM3. Ptosis without ophthalmoplegia is seen in myotonic dystrophy and congenital myopathies. Bulbar weakness with dysarthria and dysphagia is reported in myasthenia gravis, Lambert-Eaton myasthenic syndrome, and oculopharyngeal dystrophy.

Brachial Plexopathies

Upper plexus paralysis (Erb-Duchenne): C5 and C6 root damage causes impairment in shoulder abduction (deltoid and supraspinatus), external rotation of the arm (infraspinatus), elbow flexion (biceps, brachioradialis, brachialis), and forearm supination (biceps). Biceps and brachioradialis reflexes are absent. There may be hypesthesia in the lateral forearm and hand. The limb is internally rotated and adducted assuming the porter’s tip position.

Lower plexus paralysis (Dejerine-Klumpke): C8 and T1 root damage causes a claw-hand deformity with weakness of finger flexion and wasting of the intrinsic hand muscles. There may be hypesthesia in the medial arm, forearm, and ulnar aspect of the hand. A Horner syndrome accompanies T1 root injury.

Brachial Neuropathies

Anterior interosseous neuropathy (Kiloh-Nevin syndrome) causes weakness of flexion of the distal phalanges in the first (FPL), second, and third (FDP I-II) fingers. Sparing of FPL and FDP I-II in carpal tunnel syndrome results in a pinch attitude (the median version of the ulnar Froment prehensile thumb sign).

The ulnar nerve may occasionally supply the opponens pollicis, in which case this muscle is spared in CTS. Adductor pollicis and deep head of FPB are the only thenar muscles regularly supplied by the ulnar nerve.

Proximal ulnar lesions (above the elbow) result in weakness of ulnar wrist flexion and terminal phalanges of the fourth and fifth fingers. “Claw-hand” deformity only implies interossei and ulnar lumbricals paresis. Weakness of adductor pollicis results in the Froment prehensile thumb sign whereby distal flexion of the thumb occurs to increase pinch grip (“reverse” Kiloh-Nevin syndrome). Sensory deficits beyond 2 cm above the wrist localize the lesion to the T1 root, the medial cord, or the medial cutaneous nerve of arm and forearm.

Martin-Gruber anastomosis (seen in up to 31% of patients) represents axons from the median nerve crossing over the forearm to join the ulnar nerve at the wrist. The median nerve ends up innervating intrinsic hand muscles, especially the first dorsal interosseous, adductor pollicis, and hypothenar muscles.

Radial nerve (C6-T1)
Proximal to the spiral groove:		Wrist drop from retrohumeral or spiral groove lesions preserves elbow extension, triceps reflex, and sensation of the posterior forearm, but causes weakness in the brachioradialis (tested with elbow flexion when forearm is in neutral position), radial wrist extension, and finger extension, with hypalgesia restricted to the dorsolateral hand.
	Triceps (C7, C8)
	Anconeus
Below the spiral groove:
	Brachialis
	Brachioradialis (C5, C6)
	Extensor carpi radialis (ECR) (C5, C6)
Superficial branch: dorsal digital nerve
Deep: Posterior interosseous nerve
	Supinator (at the Arcade of Frohse)
	Extensor carpi ulnaris (ECU) (C7, C8)
	Extensor digitorum Extensor indicis	Posterior Interosseous Neuropathy
	Extensor digiti minimi Extensor pollicis longus Extensor pollicis brevis Abductor pollicis longus	Causes weakness of finger extension with radial deviation of the wrist when attempting to make a fist or extend the hand. Triceps, brachioradialis, and extensor carpi radialis are normal. There is no loss of sensation or reflexes.
Spiral Groove Radial Palsy
Weakness of wrist and finger extension with normal triceps strength. A bruise or scar may be present in the posterior part of the upper arm. The brachioradialis reflex may be absent. Snuffbox hypesthesia is present.
C7, C8 Root or Plexus Lesion
Weakness of triceps and finger extension with radial deviation of the wrist on attempted extension (normal extensor carpi radialis). Brachioradialis strength is normal. Triceps reflex is reduced or absent. There should be hypesthesia in the C7, C8 dermatomes.
C7, C8, T1 Root or Plexus Lesions		The brachioradialis is the key muscle to test in a patient with wrist drop: it is weak in radial nerve lesions proximal to or at the spiral groove, whereas it is normal in posterior interosseous neuropathy and C7-T1 root or plexus lesions.
As above plus weakness of finger flexors and extension of the sensory loss to the T1 dermatome (ulnar aspect of the forearm and hand). Classic causes are cervical rib (diminished arm pulse) and Pancoast tumor (Horner syndrome)^a
^aCervical spondylosis is not a cause of weakness in the small hand muscles because these are mainly supplied by T1.

Assessment of Hand Weakness

Wasting Confined to APB	Wasting Confined to FDI and ADM
Usually a median nerve lesion at wrist	Usually an ulnar nerve lesion
If there is weakness of the deep flexor of the index (FDP I) and thumb (FPL), the lesion is at the elbow (anterior interosseous nerve)	If there is weakness of the deep flexor of the little finger (FDP IV) and ulnar wrist (FCU), and loss of sensation in medial hand, the lesion is at the elbow
Wasting of the hand, areflexia, and a dissociated sensory loss (hypesthesia to pain and temperature with preservation of proprioception) in a half-cape distribution suggest syringomyelia, ependymoma, or other intrinsic lesions of the cervical and upper thoracic cord. For “ALS split hand,” see next section.

Proximal Arm Weakness Assessment

Root	Muscles	Nerve	Other Findings
C5, C6	Deltoid	Axillary	Weak radial wrist extension and absent biceps reflex
	Biceps	Musculocutaneous
	Brachioradialis	Radial
C7, C8	Triceps	Radial	Weak finger extension and absent triceps reflex
Serratus anterior (scapular fixation and rotation, long thoracic nerve) represents C5-C7 levels.

Deltoid, Biceps, and Brachioradialis Weakness

C5, C6 Cord Lesion	C5, C6 Root or Plexus Lesion
Biceps and brachioradialis reflexes are absent, but those below the level of lesion (triceps and finger flexors [C7, C8]) in the arms and legs are increased. A C5 sensory level may be present.	Biceps and brachioradialis reflexes are absent; all others are normal. Very proximal lesions involve all muscles; further down, serratus anterior will be spared, and further down still, supra- and infraspinatus will be spared. Sensory loss is dermatomal.

The “Split Hand” in Amyotrophic Lateral Sclerosis

The split-hand pattern refers to preferential wasting of the abductor pollicis brevis (APB) and the first dorsal interosseous (FDI) muscles, with relative preservation of the medial abductor digiti minimi (ADM) muscle. Thus, the ALS hand muscle wasting preferentially affects the “thenar (lateral) hand,” with relative sparing of the hypothenar muscles. It is rarely seen in diseases other than ALS. The muscles involved are innervated through the same spinal segments (C8 and T1), and FDI and ADM, which are differentially affected, are both ulnar nerve innervated.

Patient with early ALS demonstrating selective wasting of the right hand favoring thenar over hypothenar muscles. Note the incomplete fisting (right upper panel) and the resulting inability to button with that hand (right lower panel) due to loss of the pincer or precision grip.

The physiological mechanisms underlying the split hand in ALS are poorly understood. Both cortical and spinal/peripheral mechanisms may be involved. A cortical basis for the split-hand sign is based on the greater representation of the thenar muscles, APB/FDI. Motor potentials evoked by magnetic stimulation are significantly smaller in the thenar versus the hypothenar muscles, also supporting a cortical mechanism. On the other hand, peripheral axonal excitability studies have suggested that APB/FDI motor axons have more prominent persistent sodium currents than ADM axons, leading to higher axonal excitability and thereby more degeneration. Pincer or precision grip is vital to human hand function, and frequent use of thenar complex muscles may lead to greater oxidative stress and metabolic demands at both upper and lower motor neurons innervating the APB and FDI.

The split hand is a useful diagnostic sign in early ALS. Recent studies suggest that the sign has high specificity for this diagnosis and can be used to distingu ish ALS from mimic disorders.

Lumbar Plexus

Femoral nerve (L1-L4)
		Iliopsoas (hip flexor) (L1-L3)	Femoral nerve provides sensation to the medial thigh (medial cutaneous nerve of the thigh) and medial lower leg (saphenous).
	Distal to the inguinal ligament:
		Quadriceps femoris (leg extensor) (L2-L4)
		Sartorius (thigh flexor and evertor)
		Pectineus (thigh flexor and evertor)

Femoral neuropathies cause weakness of hip flexion (iliopsoas) and leg extension (quadriceps femoris), absent patellar reflex, normal hip adduction, and hypesthesia on the anteromedial thigh and leg. Possible causes are retroperitoneal hematoma and child-birth in lithotomy position. An important cause of painful femoral neuropathy is adult-onset diabetes mellitus (diabetic amyotrophy). Lesions at or below the inguinal ligament level spare thigh flexion as the femoral branches to the iliopsoas are preserved.

Obturator nerve (L2-L4), subject to obstetric injury, is responsible for thigh adduction and, secondarily, internal rotation and knee flexion (gracilis muscle).

L2-L4 radiculopathy or plexopathy causes weakness of iliopsoas, quadriceps, and hip adductors. The L2-L4 dermatome follows that of the femoral nerve.

Lateral femoral cutaneous nerve (L2-L3) injury (meralgia paresthetica) is especially characteristic in obese individuals who wear constrictive garments.

Sacral Plexus Inferior gluteal nerve (L5-S2)

supplies the gluteus maximus (hip extension)

Tibial Nerve

Gastrocnemius (S1-S2)

Soleus (S1-S2)

Popliteus

Plantaris

Main plantar flexors are located in the distal popliteal fossa (S1-S2)

Tibialis posterior (L4-L5)

Flexor digitorum longus (L5-S2)

Flexor hallucis longus (S1-S2)

Main plantar flexors and foot invertors are located in the posterior leg compartment (L4-S2)

Sensation to the lateral heel and foot is provided by the sural nerve, which forms with contributions from the common peroneal (lateral sural cutaneous).

The tarsal tunnel (formed by the lancinate ligament, which runs from the medial malleolus to the calcaneus) gives rise to the distal tibial nerve fibers (S1-S2):

Medial Plantar Nerve	Lateral Plantar Never
Abductor hallucis, flexor hallucis, flexor digitorum brevis, and the lumbricals I-II (also, skin of medial two-thirds of the sole of the foot)	Adductor hallucis, abductor digiti minimi, flexor digiti minimi, interossei, and lumbricals III-IV (also, skin of lateral one-third of the sole of the foot)

Peroneal Nerve

In the popliteal fossa, the common peroneal gives off the lateral cutaneous nerve of the calf (skin of lateral leg below the knee) and the lateral sural cutaneous nerve, which joins its medial counterpart to form the sural nerve (skin of distal posterior leg and lateral foot).

Deep peroneal (tibialis anterior)
	Tibialis anterior (L4-L5) Extensor digitorum longus (L5) Extensor hallucis longus (L5) Extensor digitorum brevis (L5) (Also, skin next to first and second toes)	Main foot dorsiflexors and toe extensors (tibialis anterior is also a foot invertor) are located in the anterior leg compartment (L4-L5)
Superficial peroneal
	Peroneus longus (L5) Peroneus brevis (L5) (Also, skin of distal leg and dorsum of the feet and toes)	Plantar evertors (L5)

Assessment of Foot Drop

Common Peroneal	L5 Radiculopathy
Weakness of dorsiflexion and eversion is more common; extensor hallucis longus weakness will confirm location. Hypesthesia occurs in lateral leg.	Weakness of dorsiflexion and inversion. Hypesthesia occurs on the lateral leg, dorsomedial foot, and large toe.
In the electrophysiologic study of foot drop, the short head of the biceps femoris is the preferred above-the-knee muscle to test. Since the peroneal division of the sciatic nerve proximal to the fibular head supplies this muscle, its involvement localizes the deficit to the sciatic nerve.

Piriformis syndrome is an entrapment syndrome of the sciatic nerve as it passes through the greater sciatic notch. It is suspected when foot drop is accompanied by buttock tenderness, sciatica reproduced on deep palpation, and leg pain worsened by internal rotation of the flexed limb. Sources as diverse as pelvic surgery, buttock trauma, wallet pressure, and toilet seat entrapment have been reported. Besides foot drop, the main features are:

Weakness of knee flexion (hamstring), foot eversion (superficial peroneal), foot inversion (tibialis anterior), foot dorsiflexion (tibialis anterior), and foot plantar flexion (gastrocnemius and soleus).
Preservation of iliopsoas, hip adductors, and quadriceps muscles
Absent ankle reflex with normal patellar reflex

Lower limb monoparesis most marked in hip flexion (iliopsoas), knee flexion (hamstrings), ankle dorsiflexion, and eversion is characteristic of weakness of corticospinal origin.

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is the prototypical acute postinfectious neurologic disorder, heralded by ascending paralysis peaking at 1 week and plateauing by 4 weeks in most. Campylobacter jejuni is the most common infection (25%-50% of adult patients). Other GBS-triggering infections include cytomegalovirus, Epstein-Barr virus, measles, influenza A virus, and Mycoplasma pneumoniae; and, more recently, enterovirus D68 and Zika virus. Areflexia and CSF albuminocytologic dissociation (proteinorrhachia without pleocytosis) are the clinical hallmarks. Autonomic dysfunction and cranial nerve involvement (commonest VII, IX-X) may each develop in half of all patients.

Very slow NCV (nerve conduction velocity), dispersed CMAP, and multifocal conduction block are the electrophysiologic correlates. Initial abnormalities may be limited to prolonged F-waves. Mononuclear inflammatory infiltrates in the endoneurium and myelin sheath cause patchy segmental multifocal demyelination. The most common GBS type is demyelinating (AIDP), but axonal forms, with potential preservation of reflexes, have been identified:

Acute motor axonal neuropathy (AMAN) or “Chinese paralytic syndrome,” most common form of GBS in Asia
Acute motor and sensory axonal neuropathy (AMSAN): more rapid onset and severe weakness; recovery is slower and incomplete
Pharyngeal-cervical-brachial (PCB) weakness

Anti-GM1b, anti-GD1a, and GalNAc-GD1a IgG antibodies can be found in these axonal forms (anti-GT1a IgG antibody is most common in the PCB variant), mostly after Campylobacter jejuni diarrhea. Anti-GD1b antibodies are associated with ataxia.

Miller-Fisher syndrome (5% of GBS) causes total external ophthalmoplegia (with pupil-sparing ptosis), ataxia, and areflexia. The presence of diplopia and the celerity of ataxia distinguish this ophthalmoplegia from mitochondrial myopathies. Anti-GQ1b IgG antibodies can be identified in this GBS variant.

Plasma exchange (PLEX) or intravenous immune globulin (IVIG) hastens recovery from GBS. Both are equally effective, but the combination is not superior to either treatment modality given alone. PLEX is technically demanding and carries a greater risk of side effects. Steroid treatment is not beneficial. Supportive care relies on intubation if FVC is <15 to 20 mL/kg, DVT prophylaxis, monitoring for autonomic instability, and PT/OT.

Chronic Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic (>2 months), progressive, or relapsing autoimmune areflexic weakness with or without cranial nerve involvement, autonomic symptoms, ataxia, and neuropathic pain, resulting from a symmetric motor/sensory radiculoneuropathy. CSF shows albuminocytologic dissociation and NCV multifocal demyelination in at least three nerves, with at least one with conduction block or temporal dispersion.^a

The variants are:

MMN: Multifocal motor neuropathy with motor conduction block and anti-GM1 and anti-GD1a antibodies presents with asymmetric distal upper extremity and differential finger extension weakness, reflecting vulnerability of terminal branches of the posterior interosseous nerve. Unlike classic CIDP, CSF protein is normal.
MADSAM: Multifocal acquired demyelinating sensory and motor neuropathy presents as a chronic mononeuropathy multiplex (Lewis-Sumner syndrome) or MMN with sensory deficits. Unlike MMN, GM1 antibodies are uncommon. The axonal variant is MASAM or multifocal acquired sensory and motor neuropathy.
DADS: Distal acquired demyelinating symmetric neuropathy is a symmetric predominantly sensory polyneuropathy whereby patients often have IgM monoclonal gammopathies with anti-MAG (myelin-associated glycoprotein) antibodies. Presence of these IgM M-proteins is associated with steroid failure.
IgG4-related nodopathy/paranodopathy is due to IgG4 antibodies to nodal and paranodal proteins, such as contactin-1 (CNTN1), neurofascin 155 (NF155), and contactin-associated protein 1 (Caspr1). This subacute CIDP/GBS variant presents with early and severe axonal invol vement and sensory ataxia and responds better to corticosteroids and rituximab than IVIg.

CIDP may also be associated with HIV, monoclonal gammopathy of undetermined significance (MGUS), or lymphoproliferative disorders such as lymphoma, Waldenström macroglobulinemia, multiple myeloma, osteosclerotic myeloma (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes—aka POEMS syndrome), and Castleman disease.

Immunosuppressive therapy is the mainstay of treatment. Prednisone, PLEX, and IVIG are variably beneficial. No consensus exists as to the best first line of intervention. Patients with pure motor CIDP and MMN do not respond or worsen with corticosteroids or PLEX. IVIG should be avoided in patients with IgA deficiency (anaphylaxis). Potential risks of other immunosuppressants are interstitial lung fibrosis (methotrexate), gout (azathioprine), nephrotoxicity (cyclosporine), and fatal hemorrhagic cystitis (cyclophosphamide).

Myasthenia Gravis

Myasthenia gravis (MG) is the most common autoimmune disorder of neuromuscular transmission. Its prevalence is estimated at 14 per 100,000 people. It manifests as fluctuating generalized weakness with preservation of muscle stretch reflexes. Autoantibodies against the nicotinic acetylcholine receptor (AChR) are present in 80% of generalized MG, against muscle-specific kinase (MuSK) in 5% to 10% (these patients tend to have neck extensor, shoulder, bulbar, and respirator weakness) and against low-density lipoprotein receptor-related protein (LRP4) in 1% to 5% (milder symptoms; may manifest purely as ocular MG). The prevalence of ocular MG is similar among patients with anti-AChR and anti-LRP4 antibodies whereas is nil in those with anti-MuSK antibodies. About 10% of patients are “triple seronegative.”

Autoimmune disorders such as rheumatoid arthritis, SLE, and pernicious anemia may be present in 5% of the patients, thymoma in 15% (30% thymoma patients develop MG), and thymic hyperplasia with proliferation of germinal centers in up to 70%. The presynaptic homologues of MG are Lambert-Eaton myasthenic syndrome (LEMS, see Paraneoplastic syndromes of the PNS in Chapter 8) and botulism (see Neurotoxicology in Chapter 4).

AChR antibodies, repetitive nerve stimulation, and single-fiber EMG are very sensitive for diagnosis. The edrophonium (tensilon) test is now rarely necessary. Drugs that impair ACh release, worsening MG, are quinine, procainamide, P-type calcium channel blockers, antibiotics, and hypermagnesemia-causing laxatives and antacids. The iatrogenic causes of autoimmune MG are D-penicillamine, interferon alpha, and bone marrow transplantation (graft-versus-host disease).

The first choice of therapy is the acetylcholinesterase inhibitor pyrido stigmine (Mestinon), given at 30 to 60 mg qid with maximal efficacy achieved at 60 mg every 4 hours. Thymectomy brings delayed improvement in 75% of seropositive patients <50 years. Prednisone (perhaps with azathioprine as a steroid-sparing drug) is used in those who fail Mestinon. IVIG (0.4 g/kg daily for 3 days) is required in refractory cases, during myasthenic crisis, or as a presurgical boost. PLEX is beneficial for those with MuSK-positive MG. The recombinant humanized monoclonal antibody eculizumab (Soliris) was recently approved by the U.S. FDA for anti-AChR antibody-positive adults with generalized MG. Efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, has also been found effective for these patients.

Myasthenic crisis (not cholinergic) is triggered by surgery, infection, or rapid withdrawal of corticosteroids. Intubation is indicated when the FVC <15 mL/kg.

Myasthenic Crisis	Cholinergic Crisis
Respiratory arrest	Fasciculations
Respiratory-based deficits: cyanosis, poor cough dysphagia	GI symptoms: abdominal cramps, diarrhea, nausea, vomiting
Secretions cannot be swallowed	Excessive salivation and lacrimation
Normal pupil	Miosis
Improves with edrophonium	Worsens with edrophonium

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS, motor neuron disease) is the most common degenerative motor neuron disease of adulthood, affecting 2/100,000/year with a 2:1 male-to-female ratio. It is recognized by the presence of upper (UMN; spasticity and corticospinal tract signs) and lower (LMN; cramps, fasciculations, progressive atrophy, and weakness) motor signs as well as dysarthria, dysphagia, and dyspnea. Average disease duration is ˜4 years. Pseudobulbar palsy (emotional incontinence) is frequent in ALS. Important spared functions are the extraocular motility, bladder and bowel (intact Onuf nucleus, a small motor neuron group in the S2 anterior horn), and sensory system. Frontotemporal dementia may coexist.

Poor prognosis is seen in older females with bulbar onset. Best prognosis in younger patients and in those with primary lateral sclerosis.

While most ALS cases are sporadic, approximately 10% show familial inheritance. The most common familial ALS is due to hexanucleotide repeat expansion in the C9ORF72 gene, ˜40%, and mutations of SOD1, TARDBP, and FUS account for 12% to 24%, 5%, and 4%, respectively. SOD1 ALS tends to have earlier age at onset and predominant lower-limb onset; TARDBP ALS a predominant upper-limb onset and longer survival (longest [>9 years] with the A315T mutation). Sporadic ALS risk is increased by intermediate expansions in ataxin-1 (>32) and ataxin-2 (>28), as well as duplications in the SMN1 (survival motor neuron 1) gene.

Differential diagnosis of ALS includes the following:

Cervical spondylotic myelopathy
Multifocal motor neuropathy with or without anti-GM1 antibodies
Inclusion body myositis
Others: spinocerebellar ataxia type 2 (SCA2), ATP13A2 mutations (juvenile-onset ALS besides Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 [CLN12]), toxins (lead, organophosphates), drugs (dapsone used for dermatitis herpetiform and malabsorption enteropathy [onset in hands, asymmetric]), infections (syphilis, borreliosis, CJD), metabolic disorders (porphyria, hyperparathyroidism, diabetes), hexosaminidase A deficiency (adult GM₂ gangliosidosis or Tay-Sachs disease), and polyglucosan body disease (GSD IV)

MRI of the spine is mandatory to exclude cervical spondylotic myelopathy. NCV and F waves are usually normal in ALS, whereas EMG shows generalized denervation (fibrillations, positive sharp waves) and neurogenic motor unit potentials. Muscle biopsy is only considered in atypical cases when inclusion body myositis is suspected. Bunina bodies are the only specific neuronal inclusions.

The antiglutamatergic agent riluzole (50 mg bid) prolongs life by about 3 months. Liver enzyme monitoring is indicated. The antioxidant edaravone (Radicava) was recently approved to slow disease progression. Palliative care includes quinine sulfate, CBZ, vitamin E, and verapamil for fasciculations and cramps; amitriptyline or dextromethorphan and quinidine sulfate (Nuedexta) for pseudobulbar affect; glycopyrrolate for drooling; percutaneous endoscopic gastrostomy (PEG) for dysphagia and weight loss; face mask for intermittent home ventilation or 24-hour mechanical ventilation via tracheostomy for dyspnea.

Atypical Motor Neuron Diseases (ALS Variants)

Disorders restricted to the upper motor neuron (UMN) must be differentiated from cervical spondylotic myelopathy, human T-cell lymphotropic virus-1 (HTLV-1)-associated myelopathy, HSP, SPS, MS, and adrenomyeloneuropathy.

Primary lateral sclerosis (PLS) has a more benign course than, although may eventually transform into, typical ALS. Corticospinal and corticobulbar involvement leads to gradually progressive spastic quadri- or paraparesis.
Hereditary spastic paraparesis (HSP) may have AD (up to 70% of “pure” cases), AR, and X-linked modes of inheritance. AD form expresses at an older age (after 35 years) and is slower in progression (see next section).
Lathyrism refers to the selective UMN glutamatergic toxicity caused from the neurotoxin of Lathyrus sativus, chickpea, widely consumed in famine-stricken countries where this drought-resistant crop can be cultivated.

Disorders restricted to the lower motor neuron (LMN)

Progressive muscular atrophy (PMA) affects young males with slowly progressive asymmetric focal weakness of distal limbs. The mean duration ranges from 5 to 15 years. It can be confused with IBM.
X-linked bulbospinal neuronopathy (Kennedy disease) affects only males with predominantly bulbar weakness (prominent tongue and chin fasciculations) but lesser progression to dysphagia and dysarthria. Gynecomastia occurs in up to 90% of cases. Other endocrinopathies are testicular atrophy and diabetes mellitus. Sensory involvement may occur. There exists CAG repeat expansion in the androgen receptor gene.
Multifocal motor neuropathy (MMN) presents in older males as asymmetric focal weakness of distal limbs, with relative preservation of muscle bulk. It results from peripheral motor fiber demyelination instead of motoneuronal cell bodies. EMG shows conduction block in various nerves. High titers of anti-GM1 ganglioside antibodies are present. Half the patients respond to periodic high-dose IVIG but not to prednisone.
Monomelic amyotrophy (MMA) aka Hirayama disease is a male-predominant, slow-progressing, self-limited “benign focal SMA,” often restricted to adjacent myotomes of one arm with limb wasting but relatively well-preserved strength. This disorder is apparently sporadic and more common in Japan and India.
Adult-onset spinal muscular atrophy (SMA type IV) is distinguished by a family history (70% AR as in the childhood-onset SMAs and 30% AD; deletions in the 5q chromosome are rare) and a slowly progressive and symmetric limb-girdle weakness of the legs. Survival is over 20 years. The antisense oligonucleotide nusinersen (Spinraza) has been approved for children and adults with SMA.
Postpolio muscular atrophy is a focal and asymmetric muscle weakness that progresses from same regions previously affected by polio which had been stable for at least 10 years.

Other clinical ALS variants include brachial amyotrophic diplegia (flail arm variant) and the pseudopolyneuritic variant (flail leg syndrome).

Hereditary Spastic Paraparesis

Hereditary spastic paraparesis (HSP) is a genetically heterogeneous syndrome of progressive paraparesis without other features (uncomplicated HSP) or with other deficits (complicated HSP). Degeneration of terminal long spinal axons is implicated.

Selected Uncomplicated HSP (“Pure” Spastic Paraparesis)

Autosomal dominant	SPG4 SPAST	2p	Atypical complicated presentations include nystagmus, head tremor, late-onset cognitive decline, lower-motor neuron features.
	SPG3A ATL1	14q	Besides UMN and pes cavus, scoliosis, mild intellectual disability, and optic atrophy may occur. Thin corpus callosum has been described.
	SPG6 NIPA1	15q	A complicated phenotype includes seizures and postural tremor in the upper limbs.
	SPG10 KIF5A	12q	A complicated phenotype includes parkinsonism, cerebellar ataxia, cognitive decline, sensorimotor peripheral neuropathy with distal amyotrophy, pes cavus, and scoliosis. Allelic: Charcot-Marie-Tooth type 2-like.
	SPG13 HSPD1	2q	Allelic condition: autosomal recessive hypomyelinating leukodystrophy type 4.
	SPG31 REEP1	2p	Dysphagia, pes cavus, and distal amyotrophy. Allelic condition: distal hereditary motor neuronopathy type VB.
	SPG43 C19ORF12	19q	Severe atrophy of the limbs (ALS-like), contractures, and pes cavus. Allelic condition: neurodegeneration with brain iron accumulation (NBIA) type 4 or mitochondrial protein-associated neurodegeneration (MPAN). Brain MRI may show the medial medullary sign in the pallidum.
Autosomal recessive	SPG5A CYP7B1	8q	A complicated phenotype may include cerebellar ataxia, spastic ataxia, pes cavus, and optic atrophy.
	SPG25 Unknown	6q	Aka, disk herniation with spastic paraplegia syndrome (familial intervertebral disk disease). Spinal disk herniation is a hallmark of this subtype.
	SPG28 DDHD1	14q	Pes cavus, and scoliosis. It has been described in consanguineous families from Morocco and Turkey.
	SPG30 KIF1A	2q	A complicated phenotype may include cerebellar ataxia and mild distal axonal neuropathy. It has been described in consanguineous families from Algeria and Palestine.
	SPG39 PNPLA6	19p	Marked distal arm and leg amyotrophy with motor axonopathy on NCV (˜Troyer syndrome as in SPG20). Brain MRI: cerebellar and thoracic spinal cord atrophy.
SPG4/spastin is the single most common form of HSP, pathogenic by haploinsufficiency. Other SPGs not listed due to their description in only one or two families.

Selected Complicated HSP (Associated With Other Deficits)

Autosomal dominant	SPG9A ALDH18A1	10q	Motor neuronopathy (ALS-like phenotype), cataracts, short stature, and cerebellar ataxia
Autosomal dominant	SPG17 BSCL2	11q	Amyotrophy of hand muscles (Silver syndrome) with later distal lower limb amyotrophy
Autosomal recessive	SPG7 SPG7	16q	Axonal neuropathy, optic atrophy, CPEO, dysarthria, dysphagia, cerebellar atrophy (spastic ataxia)
	SPG11 SPG11	15q	Intellectual disability, dysarthria, neuropathy, parkinsonism, and thin corpus callosum
	SPG14 Unknown	3q	Intellectual disability and distal motor neuropathy with pes cavus
	SPG15 ZFYVE26	14q	Pigmentary maculopathy, hearing loss, dysarthria, distal amyotrophy (axonal and demyelinating polyneuropathy), cerebellar ataxia, epilepsy, and juvenile levodopa-responsive parkinsonism. Brain MRI shows thin corpus callosum (like SPG11).
	SPG26 B4GALNT1	12p	Intellectual disability, peripheral neuropathy, distal amyotrophy, pes cavus, and eventually, cerebellar ataxia, nystagmus, cataracts, scoliosis, and dystonia
	SPG20 SPG20	13q	Troyer syndrome: spastic paraparesis and distal muscle wasting in hands and feet. Dysmorphic features include limb contractures, hyperextensible hand joints, clinodactyly, camptodactyly, and pes cavus.
	SPG35 FA2H	16q	Aka, fatty acid hydroxylase-associated neurodegeneration (FAHN): cerebellar ataxia with dystonia, dysarthria, strabismus, cognitive decline, optic atrophy, and seizures. Brain MRI shows T2 pallidal hypointensity, white matter hyperintensity (capsular sign), thin corpus callosum, and atrophy of cerebellum.
X-linked	SPG1 L1CAM	Xq28	Intellectual disability and aphasia with adducted thumbs (secondary to absence of extensor pollicis longus), short stature, and kyphoscoliosis. Brain MRI shows callosal agenesis and hydrocephalus.
	SPG2 PLP1	Xq28	*Proteolipid protein* (intrinsic myelin protein) causes quadriplegia, nystagmus, and seizures with leukoencephalopathy.
	SPG16 Unknown	Xq11	Nonfluent aphasia, poor vision, mild intellectual disability, and facial and hand dysmorphism
	SPG22 SLC16A2	Xq13	Neonatal hypotonia evolving to spastic paraparesis, cerebellar ataxia, intellectual disability, dystonia, and amyotrophy. Other features may include microcephaly, large ears, marfanoid habitus, and pectus excavatum. Brain MRI shows mild hypomyelinating leukodystrophy.
PLP1 mutations cause both Pelizaeus-Merzbacher disease (X-linked PMD) and progressive paraparesis (X-linked HSP). SPG, spastic gait locus. The “ears of the lynx” sign, FLAIR hyperintensity in the forceps minor of the corpus callosum, is highly specific for SPG11 and SPG15.

Approach to a Patient With Suspected Hereditary Spastic Paraparesis

Spastic paraparesis or tetraparesis, with or without sphincter disturbance, and with or without family history, after negative screening for acquired neurometabolic diseases (e.g., adrenomyeloneuropathy [X-ALD]).

^* HSPs with lower-motor neuron disease (ALS-like phenotype) include SPG4, SPG9A, SPG11, SPG14, SPG15, SPG17, SPG20, SPG21, SPG26, SPG38, SPG39, SPG43, SPG62, and SPG64.

IFIH1 gene (2q24.2) leads to an HSP associated with multisystemic inflammation, including interstitial lung disease, oral ulceration, diffuse hair loss, dermatomyositis, Raynaud phenomenon, and arthritis.

Spinal Cord Pathologies per Compartment

Intradural Intramedullary Lesions

Characterized by apparent widening of the cord in two projections (90° apart):

Ependymoma
Astrocytoma

(adults)

(children)

Most common primary SC tumors

Enhancement is almost a rule

Hemangioblastoma
AVM, cavernous malformations
Hematoma
Syringomyelia, hydromyelia
Cord edema
Infarcts (diabetics having aortic surgery)
Abscess (myelitis)
Demyelination (MS, ADEM, NMOSD)
Lipoma, cysts

Foix-Alajouanine syndrome: subacute venous hypertensive congestive myelopathy due to impaired venous outflow as a result of an dural arteriovenous fistula (DAVF) at the lower thoracic and/or lumbosacral levels. Patients are usually older than 50 years. Spinal cord angiography is the diagnostic test of choice.

Intradural Extramedullary Lesions

Characterized by widening of the CSF gutter on the side of the lesion, displacement of the cord away from it, and “capping defect” in the contrast: