History

Fact Explanation
Introduction to the disease The hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder that characterized by lower extremity spasticity and weakness. There are several classifications of HSP. It can be classify clinically as uncomplicated or complicated and genetically by mode of inheritance,causative mutation as well as chromosomal locus.[1].
Family history of HSP Since it is genetically heterogeneous family history may play an important role. It can be inherited in autosomal dominant, autosomal recessive, X-linked as well as mitochondrial inheritance manner.[1].
Lower extremity weakness and spasticity This is the most predominant feature of HSP which occurs in variable proportions. So that it resembles spastic diplegic cerebral palsy if symptoms start at very early childhood. If symptoms begin later it may progress slowly and steadily.Progressive lower extremity spastic weakness is a characteristic feature of pure HSP.[1].
Difficulty in walking Affected individuals commonly develop difficulty in walking. It may either be non progressive or worsen insidiously.So that the patient often need wheelchairs, canes and walkers.[1].
Urinary sphincter disturbance Seen among 50% of patients. This commonly manifest as a combination of as urgency, frequency and hesitancy. Commonly seen among patients with long standing disease.[2]. Urgency is commonly seen in classic HSP. Occurs due to hypertonic urinary bladder. This can be either non progressive or slowly progressive.[1]
Paresthesia Paresthesia in lower extremity can recognized in pure HSP.[1].
Sensory neuropathy and Ulcers Found in complicated HSP. Sensory neuropathy either can be asymptomatic which detect only by clinical examination, childhood onset or adult onset. Chronic painless cutaneous ulcers and neuropathic bone resorption found to be occur in some patients in their early childhood. Long standing established spastic paraparesis may cause less severe form of tropic skin changes and ulcers on the feet in their adult life.[2].
Seizures / Epilepsy Found to be occur in complicated HSP.[1]. Studies has bee found epilepsy syndromes and HSP seem to be closely associated. Exact pathology is not clear and there is no exact association with specific seizure type but myoclonic, simple partial, complex partial, as well as generalised epilepsy have been reported. HSP also found to inherited in mitochondrial inheritance manner and epilepsy is a characteristic feature of those mitochondrial diseases.[2].
Intellectual disability Recognized feature of complicated HSP.[1].
Dementia Seen among patients with complicated HSP.[1]. It has also been reported in both autosomal dominant as well as recessive families. Some studies suggest that sub cortical dementia may characterize the complicated HSP phenotype of spastic paraplegia with dementia.[2].
Microcephaly The presence of microcephaly suggestive of early onset illness affecting brain growth and development. But it is found to be uncommon in adult onset HSP because they initially had normal brain growth and development so that the normal head size.[3].
Amyotrophy Seen in patients with complicated HSP. Wasting of small muscles of the hand can be recognized. Sometimes it may resembles hereditary motor and sensory neuropathy. [1],[2].
Dysmetria Occurs due to cerebellar involvement. A trace of terminal dysmetria may sometimes found in the upper limbs However affected individuals do not show more florid cerebellar signs.[2].
Ataxia Can be seen in complicated HSP due to underline cerebellar involvement.[1],[2].
Dysarthria Recognized feature of complicated HSP. Occurs due to cerebellar involvement. Speech impairments and delayed language development found to be occurred.[3],[2].
Icthyosis Seen in complicated HSP. Associated with mental retardation and occasionally with pigmentary macular degeneration.[2].
Pes cavus It is an uncommon finding. Finding itself reflect the duration as well as severity of the disease.[2].
References
  1. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682
  2. MCDERMOTT C.. Hereditary spastic paraparesis: a review of new developments. [online] 2000 August, 69(2):150-160 [viewed 25 September 2014] Available from: doi:10.1136/jnnp.69.2.150
  3. KOUL R, AL-MURSHEDI FM, AL-AZRI FM, MANI R, ABDELRAHIM RA, KOUL V, ALFUTAISI AM. Clinical Spectrum of Hereditary Spastic Paraplegia in Children: A study of 74 cases Sultan Qaboos Univ Med J [online] 2013 Aug, 13(3):371-379 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749020

Examination

Fact Explanation
Spastic weakness Occurs due to corticospinal tract deficit that affecting both lower extremities. Spasticity is maximally seen in muscles such as hamstrings, quadriceps, adductors, gastrocnemius and soleus Where the weakness is commonly demonstrated in iliopsoas, hamstring, and tibialis anterior muscles. It can be variable. Some may have spasticity without demonstrable weakness, whereas the others may have spasticity and weakness in similar proportions.[1].
Hyperreflexia, Commonly seen in lower limbs due to deficit in corticospinal tract. Axon degeneration maximaly at the distal ends of the corticospinal tracts is the underline pathology.[1]. In early part of the disease mild hyperreflexia in upper limb can be demonstrated but the upper limb involvement is relatively uncommon in HSP. [2].
Extensor plantar response Disease is typically associated with bilateral extensor plantar responses. This is also a manifestation of corticospinal tract deficit.[1].
Mild sensory impairment Sensory abnormalities seen in the lower limbs. It is seen among 10%-65% of cases of pure HSP found to have this specially in case of long standing disease.[2]. Axon degeneration found to be occur in lesser extent, at the distal ends of dorsal column fibers.So that mild impairment of vibration sensation seen in the distal lower extremities.[1]. Diminished joint position sense in the extremities of the lower limbs also has been reported.[2].
Absent ankle jerks It is an uncommon sign. It occurs due to central axonopathy rather than due to peripheral nerve involvement.[2].
Muscle wasting Mild muscle wasting is well recognised feature although uncommon in HSP. It is commonly seen in patients who have had the disease for over 10 years. Distal muscles in the lower limbs, usually the small muscles of the foot and tibialis anterior are the muscles that commonly get affected.[2].
Dystonia, rigidity and choreoathetosis They are Extrapyramidal signs ,detected in complicated HSP.[2].
Retinal changes Optic atrophy and retinal degeneration seen in some patients with complicated HSP.[2].
Cranial nerve examination findings Normal cranial nerve function and no evidence of corticobulbar tract involvement are the important negative findings on examination.[2].
Peripheral nervous system examination findings Peripheral nerve involving, peripheral neuropathy can be seen in complicated HSP. It has been associated with neuropathic ulcers.[2].
Higher function assessment findings Impairment of higher functions seen in complicated HSP. Defective recent memory, poor perceptual speed, poor visuomotor coordination, impairment of attention and forgetfulness found in affected individuals. But they do not usualy get dysphasia, agnosia, and dyscalculia like features, which suggestive of major cortical involvement.[2].
Neurological evaluation of hypertonic bladder Hypertonic urinary bladder is a feature of classic HSP.[1]. Neurological examination should include mental status, reflexes, strength, and sensation including sacral dermatomes to determine whether there are other neurologic conditions contribute to this pathology.[3].
References
  1. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682
  2. MCDERMOTT C.. Hereditary spastic paraparesis: a review of new developments. [online] 2000 August, 69(2):150-160 [viewed 25 September 2014] Available from: doi:10.1136/jnnp.69.2.150
  3. DORSHER PETER T., MCINTOSH PETER M.. Neurogenic Bladder. Advances in Urology [online] 2012 December, 2012:1-16 [viewed 26 September 2014] Available from: doi:10.1155/2012/816274

Differential Diagnoses

Fact Explanation
Amyotrophic lateral sclerosis It is a progressive neurodegenerative disease which involves both upper motor neurons and lower motor neurons. Hyperreflexia, extensor plantar response and increased muscle tone are the recognized UMN signs where as the weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations are the recognized LMN signs. Affected individuals may present with focal weakness of the extremities such as stumbling or poor handgrip or bulbar findings such as dysarthria and dysphagia. The mean age of onset around 56 years if there is no associated family history. But it may occur 10 years earlier if there is a positive family history.[1].
Spastic diplegic cerebral palsy If HSP symptoms begin to start in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy.Spasticity in lower limb is the characteristic feature. Increased tone, exaggerated tendon jerks can be seen.It causes impairment of activities of daily living such as gait, feeding, washing and dressing. Painful joints, joint contracture and hip dislocation can occur in severe form of disease.[2],[3].
Cervical spondylosis It can be organized into three clinical syndromes including Type I Syndrome which called Cervical Radiculopathy, Type II Syndrome or Cervical Myelopathy and Type III Syndrome also known as Axial Joint Pain.Cervical radiculopathy give rise to upper extremity signs and symptoms correspond to a specific nerve root.It may cause reflex, motor, and sensory loss. C6 nerve root and the C7 nerve root commonly get affected. C6 deficit icauses decreased bracialradialis reflex, weakness of the biceps muscle, and pain and/or paresthesias radiating down the arm to the thumb and index finger where as C7 root involvement causes loss of the triceps reflex, pain and/or paresthesias radiating to the middle finger and weakness of the triceps muscle. In severe form of Cervical Myelopathy causes muscle weakness in all 4 limbs with sensory disturbances.Pathological reflexes are also present. Hoffmann's sign and Babinski's sign also can be seen. Type III syndrome is characterized by neck pain which radiates to the medial scapula, chest wall, shoulder area, or head.[4].
Krabbe disease It is characterized by infantile onset progressive neurological deterioration and death before the age two years in 85%-90% of individuals. Disease onset can occur around the age of one year or fifth decade with slow progression of the disease.Extreme irritability, spasticity, and developmental delay are the recognized features in infant and children. Progressive psychomotor regression can be seen.Weakness, loss of vision, and intellectual regression can recognized in some affected individuals.[5].
Spinocerebellar ataxia It is a autosomal dominant cerebellar disease characterized by loss of cerebellar cells.It can also inherited in autosomal recessive as well as X-linked manner.Ataxia, or irregular movement due to loss of neural control are commonly seen.other symptoms occurs due to loss of brainstem and spinal cord function. There are several sub types of spinocerebellar ataxia.The symptoms and signs vary according to the sub type. Marked loss or slowing of saccadic eye movements, dementia, as well as peripheral neuropathy recognized in SCA 2.Coarse gaze-evoked nystagmus, poor suppression of eye movement by vision, downbeat nystagmus on lateral gaze, can seen in SCA 6. The SCA7 is found to be associated with retinopathy or blindness where as the SCA 8 may cause hyperreflexia, decreased sense of vibration, as well as ataxic dysarthria.[6].
Progressive multiple sclerosis MS is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system of unknown etiology. Peak age of onset in Primary progressive MS is around 40 years. Women get affected twice common than men. Recognized features include sensory disturbance of the limbs , partial or complete visual loss , acute and subacute motor dysfunction of the limbs gait disturbances and diplopia.[7].
Dopa responsive dystonia It is characterized by childhood-onset dystonia. It has a dramatic response to administration of low-doses of oral levodopa. The age of onset is around 6 years and they may present with gait disturbance which may caused by lower limb dystonia with diurnal variation that may gradually progression to generalized dystonia. Most of them have positive family history.Normal sensory, cerebellar as well as intellectual functions can be seen.[8].
Neurosyphilis Classically, the neurological complications of syphilis found to be associated with tertiary disease. the early symptoms of neurosyphilis may occur either simultaneously with primary or secondary syphilis, or it may follow resolution of secondary syphilis. Fever, headache, nausea, vomiting, and stiff neck are the manifestations of acute meningitis.Blurred vision photophobia, visual disturbances as well as hearing loss, and facial weakness occurs due to cranial nerve involvement. Numbness and pain in the extremities and uveitis reported in some cases.Memory loss and mental confusion rarely found in early stage of neurosyphilis.[9].
Subacute combined degeneration of the spinal cord SCD is caused by vitamin B12 deficiency.It affects the posterior and lateral columns of the spinal cord. This causes reduction of nerve transmission giving rise to various clinical manifestations such as paresthesias, loss of vibratory sensation, and proprioception.Severe weakness, spasticity, clonus, paraplegia, and urinary and fecal incontinence resulted due to progression of disease.[10].
References
  1. KINSLEY L, SIDDIQUE T, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Amyotrophic Lateral Sclerosis Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301623
  2. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682
  3. LUNDY C, LUMSDEN D, FAIRHURST C. Treating complex movement disorders in children with cerebral palsy Ulster Med J [online] 2009 Sep, 78(3):157-163 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773587
  4. VOORHIES RM. Cervical Spondylosis: Recognition, Differential Diagnosis, and Management Ochsner J [online] 2001 Apr, 3(2):78-84 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116771
  5. WENGER DA, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Krabbe Disease [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301416
  6. POWELL A, CHANDRASEKHARAN S, COOK-DEEGAN R. Spinocerebellar Ataxia: Patient and Health Professional Perspectives on Whether and How Patents Affect Access to Clinical Genetic Testing Genet Med [online] 2010 Apr, 12(4 Suppl):S83-S110 [viewed 25 September 2014] Available from: doi:10.1097/GIM.0b013e3181d67e44
  7. STüVE O, OKSENBERG J, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Multiple Sclerosis Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301492
  8. SOMA V, MOHAMMED HS, RIYAS E, MURUGESAN K. Dopa-Responsive Dystonia in a Ten-Year-Old Girl J Family Med Prim Care [online] 2012, 1(2):151-152 [viewed 25 September 2014] Available from: doi:10.4103/2249-4863.104988
  9. LAFOND RE, LUKEHART SA. Biological Basis for Syphilis Clin Microbiol Rev [online] 2006 Jan, 19(1):29-49 [viewed 26 September 2014] Available from: doi:10.1128/CMR.19.1.29-49.2006
  10. MARSHALL R, MILBURN JM. Clinical Images - A Quarterly Column: Subacute Combined Degeneration of the Spinal Cord Ochsner J [online] 2013, 13(2):183-185 [viewed 26 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684324

Investigations - for Diagnosis

Fact Explanation
Magnetic resonance imaging (MRI) of the brain and spinal cord Diagnosis often established by clinical history, examination, positive family history rather than going for investigations. Investigations are useful in excluding alternative diagnoses such as cervical/lumbar spondylosis primary or secondary neoplasms,and diplegic cerebral palsy etc, but they do not otherwise add a diagnostic certainty to HSP.MRI of the brain and spinal cord are usually normal in HSP patients.[1],[2].White matter abnormality as well as thin corpus callosum are MRI brain findings of some patients with complicated HSP.[1].Thinning of the cervical and thoracic spinal cord has been found in some patients with HSP.[3].
Nerve conduction studies Found to be normal in most cases of HSP.[2].
EMG Also found to be normal in most cases of pure HSP.[2].
CSF analysis It is usually unremarkable in HSP. However increased protein concentrations in complicated families as well as raised homocarnosine concentrations occasionally have been reported.[2].
Molecular genetic testing It has been increasingly available and particularly useful to confirm a clinical diagnosis of HSP. [1].The most common genes associated with recessive HSP are SPG5A, , SPG11,SPG7, as well as SPG15.2. [3]. However currently it does not include all genes known to cause HSP, so that absence of an identified mutation in a gene known to cause HSP itself does not exclude the diagnosis of HSP.[1].
Syphilis serology Performed to exclude neurosyphilis.[2]
Serum Vitamin B12 level Subacute combined degeneration of the cord due to vitamin B 12 deficiency may resembles HSP. So this investigation is carried out to exclude the presence of subacute combined degeneration of the cord .[2].
References
  1. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682
  2. MCDERMOTT C.. Hereditary spastic paraparesis: a review of new developments. [online] 2000 August, 69(2):150-160 [viewed 25 September 2014] Available from: doi:10.1136/jnnp.69.2.150
  3. KOUL R, AL-MURSHEDI FM, AL-AZRI FM, MANI R, ABDELRAHIM RA, KOUL V, ALFUTAISI AM. Clinical Spectrum of Hereditary Spastic Paraplegia in Children: A study of 74 cases Sultan Qaboos Univ Med J [online] 2013 Aug, 13(3):371-379 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749020

Investigations - Fitness for Management

Fact Explanation
Full blood count Since some patients have to undergo orthopedic surgeries to release contractures, the baseline investigations such as FBC should be carried out for fitness assessment. [1].
Fasting blood sugar Performed in individuals who undergo orthopedic surgeries to assess fitness.[1].
References
  1. REID E. Pure hereditary spastic paraplegia. J Med Genet [online] 1997 Jun, 34(6):499-503 [viewed 26 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1050975

Investigations - Screening/Staging

Fact Explanation
Prenatal Testing If the disease causing mutation has been identified in an affected family member, this test can be carried out in pregnancies to assess the risk of fetus. It can be performed either testing for this disease/gene or custom prenatal testing.[1].
References
  1. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682

Management - General Measures

Fact Explanation
Physiotherapy There is no specific treatment either to prevent or reverse nerve degeneration in HSP. So that current management mainly targeting on reducing symptoms, improving balance and strength, as well as agility.Daily regimen of physical therapy is carried out. It may useful to improve cardiovascular fitness, gait,maintain and improve muscle strength and also to reduce spasticity.[1].
Occupational therapy Management of these HSP should be multidisciplinary approaches involving several specialties such as physiotherapist as well as occupational therapist etc..[2]. Assistive walking devices such as wheelchairs and assistive devices to improve functional gait such as ankle-foot orthotic devices can be provided.[1].
Genetic councelling It is a process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.Since disease is genetically heterogeneous, genetic counselling is a must. Patient and family members should informed about pattern of inheritance, risk of them to get disease, importance of genetic testing as well as related of family planing issues.[1].
Proper counselling ,patient and family education. Once diagnosis is established, patient should be properly counselled. The should inform about the inheritance pattern of the disease, symptoms, possible complications as well as importance of follow up. Educate the family members that this is a chronic disease and patient always need their helping hand to do their day today works. And make a proper plan for future follow up.[1].
References
  1. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682
  2. KOUL R, AL-MURSHEDI FM, AL-AZRI FM, MANI R, ABDELRAHIM RA, KOUL V, ALFUTAISI AM. Clinical Spectrum of Hereditary Spastic Paraplegia in Children: A study of 74 cases Sultan Qaboos Univ Med J [online] 2013 Aug, 13(3):371-379 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749020

Management - Specific Treatments

Fact Explanation
Baclofen Some patients show increase functional activity when treated with antispastic drugs such as the GABA agonist baclofen or newer alternatives.Oral or intrathecal Baclofen can be used. Other drugs include tizanidine and dantrolene which also reduce muscle spasticity. [1],[2].
Botox injections Intramuscular botulinum toxinfound to be improve function in selected group of patients.[1]. It is also useful in reducing muscle spasticity.[2].
Oxybutynin It is an antimuscarinic drug. It is a tertiary amine that has anticholinergic, spasmolytic,as well as local anesthetic properties. It causes relaxation of the smooth muscle by acting as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors on the detrusor muscle of the bladder.[3].It is reduce urinary urgency.[2].The frequency and severity of the side effects are dose dependent and untreated narrow-angle glaucoma urinary retention as well as severely decreased gastric motility conditions considered as contraindications to oxybutynin.[3].
Orthopaedic surgery Performed to release of contractures and tenotomie. But they may rarely have a role.[1].
References
  1. REID E. Pure hereditary spastic paraplegia. J Med Genet [online] 1997 Jun, 34(6):499-503 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1050975
  2. FINK JK, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hereditary Spastic Paraplegia Overview [online] 1993 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301682
  3. MCCRERY RJ, APPELL RA. Oxybutynin: an overview of the available formulations Ther Clin Risk Manag [online] 2006 Mar, 2(1):19-24 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1661647