Hyperekplexia

An unusual source of unsteadiness (not dizziness), is an excessive startle reflex. This goes under the very obscure and difficult to spell name of "hyperekplexia".   These people are unsteady because they develop uncontrollable spasms or postures of their body, usually as a result of a loud noise or perhaps an emotionally disturbing event.  This can occasionally cause unsteady gait (Rouco et al, 2014) but more commonly results in individuals who adopt unusual body postures after startle.   Intellectually, these are interesting conditions as there are a myriad of possible explanations (see below). Practically though, they are almost all  treated similarly with benzodiazepine type drugs.   There are many medical publications about Hyperekplexia or excessive startle (262 as of 2020).  Hyperekplexia was recently reviewed by Saini and Pandey (2020). This page is an online review of literature about hyperekplexia, particularly concerning situations where it might disturb balance.

Hyperekplexia manifests as eye blinking and a flexion of the trunk to unexpected innocuous (particularly auditory) stimuli.  It typically does not habituate.  It is one of the "startle" syndromes which also includes neuropsychiatric startle and startle induced epilepsy. (Bakker et al, 2006).  While auditory stimuli can also cause dizziness in persons with ear disorders (such as Superior canal dehiscence), these disorders are easily differentiated by the strong trunk movements seen in Hyperekplexia.

Causes of Hyperekplexia

Hyperekplexia is divided into acquired and congenital forms.  The congenital forms are mainly due to genetic defects in the glycine receptor, due to loss of function, but may also be due to complex disorders (see below). The acquired forms can involve processes that affect the glycine receptor, as well as psychological disturbances involving anxiety and unusual responses to startle, and miscellaneous neurological illnesses.

Laboratory findings in  Hyperekplexia

The causes of hyperkplexia are diverse, and the literature offers a large number of tests, sometimes found positive in cases here and there.  An MRI and EEG seems rather reasonable, looking for structural brainstem causes, and brain disturbances with abnormal excitability (such as Jakob Creutzfeldt).  Genetic testing may be productive in cases with early childhood onset (which leaves out the acquired ones). Antibody testing would seem most appropriate for severe and progressive cases (such as PERM -- see below).

Differential Diagnosis of Hyperekplexia

• Genetic causes -- these are generally very early onset in life.  One does not need to test for these in cases acquired later in life.
• Specific mutations involving the glycine receptor
• GLRA1 (about 60%)
• GLRB (12-14%)
• SLC6A5 (25%)
• Complex neurodevelopmental conditions with an excessive startle response (see Balint and Thomas (1993, and updates) for a detailed listing)
• Autoimmune -- if these are found, "immunotherapy" may be offered.
• Glycine receptor antibodies  such as in PERM -- progressive encephalomyelitis with rigidity and myoclonus. (Carvajal-Gonzalez et al, 2014),
• GAD antibodies (these are very common in other disorders, such as diabetes)
• amphiphysin antibodies
• DPPX antibodies
• Psychological (e.g. see Howard and Ford, 1992) -- this is usually a "wastebasket" diagnosis -- similar to "no other reasonable explanation." 
• Anxiety
• Tic disorder (Gilles de la Tourette) -- this may be genetic or autoimmune.
• Culture specific disorders involving exaggerated startle responses (Bhidayasiri and Truong, 2011)
• Jumping Frenchmen of Maine among the Franco-Canadian lumberjack communities
• Latah in Southeast Asia
• Focal neurological disturbances
• Post-anoxic myoclonus, infarct, hemorrhage, medullary compression, neurodegeneration,  MS
• Startle epilepsy
• Paroxysmal kinesiogenic choreoathetosis -- symptoms are induced by movement.
• Infections
• Tetanus, which prevents release of glycine
• Creutzfeldt-Jakob disease (cortical hyperexcitability due to this prion disorder) (Graveline et al, 2019)
• Subacute sclerosing panencephalitis
• Other encephalitus (e.g. Fenzi et al, 1988)
• Strychnine poisoning (this is a inhibitor of the glycine receptor)

Treatment of Hyperekplexia

 The main treatment for hyperekplexia is benzodiazepines, such as low dose clonazepam.  Other drugs that have been tried include seizure medications (e.g carmabazepine, phenytoin, valproate, levetiracetam, piracetam, phenobarbital).  (Bakker et al, 2006; Dooley and Andermann, 1989; McAbee 2015)

Summary:

Hyperekplexia is a rare cause of unsteady gait and posturing.  It is treated with low dose clonazepam.

References:

• Bakker, M. J., et al. (2006). "Startle syndromes." Lancet Neurol 5(6): 513-524.
• Bakker, M. J., et al. (2009). "Clonazepam is an effective treatment for hyperekplexia due to a SLC6A5 (GlyT2) mutation." Mov Disord 24(12): 1852-1854.
• Balint, B. and R. Thomas (1993). Hereditary Hyperekplexia Overview. GeneReviews((R)). M. P. Adam, H. H. Ardinger, R. A. Pagon et al. Seattle (WA).  This article is available online and has been updated.
• Bhidayasiri, R. and D. D. Truong (2011). "Startle syndromes." Handb Clin Neurol 100: 421-430.
• Carvajal-Gonzalez, A., et al. (2014). "Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes." Brain 137(Pt 8): 2178-2192.
• Dooley, J. M. and F. Andermann (1989). "Startle disease or hyperekplexia: adolescent onset and response to valproate." Pediatr Neurol 5(2): 126-127.
• Fenzi, F., et al. (1988). "Anatomical and clinical study of a case of subacute encephalomyelitis with hyperekplexia syndrome." Ital J Neurol Sci 9(5): 505-508.
• Graveline, J., et al. (2019). "Creutzfeldt-Jakob disease presenting with encephalopathy, rigidity, and hyperekplexia." Neurol Clin Pract 9(5): e36-e38.
• Howard, R. and R. Ford (1992). "From the jumping Frenchmen of Maine to post-traumatic stress disorder: the startle response in neuropsychiatry." Psychol Med 22(3): 695-707.
• McAbee, G. N. (2015). "Clobazam-clonazepam combination effective for stimulus-induced falling in hyperekplexia." J Child Neurol 30(1): 91-92.
• Rouco, I., et al. (2014). "Sporadic hyperekplexia presenting with an ataxic gait." J Clin Neurosci 21(2): 345-346.
• Saini, A. G. and S. Pandey (2020). "Hyperekplexia and other startle syndromes." J Neurol Sci 416: 117051.